New Compounds

ABSTRACT

The present invention provides new compounds of formula Ia and Ib: 
     
       
         
         
             
             
         
       
     
     as well as a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

FIELD OF THE INVENTION

The present invention relates to new compounds of formula Ia and Ib, asa free base or a pharmaceutically acceptable salt thereof, topharmaceutical formulations containing said compounds and to the use ofsaid compounds in therapy. The present invention further relates to aprocess for the preparation of compounds of formula Ia and Ib and to newintermediates used therein.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two isoforms (α and β), which are encoded by distinct genesbut are highly homologous within the catalytic domain. GSK3 is highlyexpressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eIF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on serine 9 residue and inactivates it.

Alzheimer's Disease (AD) dementias, and taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction andneuronal death, neurofibrillary tangles and senile plaques consisting ofamyloid-β deposits. The sequence of these events in AD is unclear, butare believed to be related. Glycogen synthase kinase 3β (GSK3β) or Tau(τ) phosphorylating kinase selectively phosphorylates the microtubuleassociated protein τ in neurons at sites that are hyperphosphorylated inAD brains. Hyperphosphorylated protein z has lower affinity formicrotubules and accumulates as paired helical filaments, which are themain components that constitute neurofibrillary tangles and neuropilthreads in AD brains. This results in depolymerization of microtubules,which leads to dying back of axons and neuritic dystrophy.Neurofibrillary tangles are consistently found in diseases such as AD,amyotrophic lateral sclerosis, parkinsonism-dementia of Gaum,corticobasal degeneration, dementia pugilistica and head trauma, Down'ssyndrome, postencephalatic parkinsonism, progressive supranuclear palsy,Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-O toprimary hippocampal cultures results in hyperphosphorylation of τ and apaired helical filaments-like state via induction of GSK3β activity,followed by disruption of axonal transport and neuronal death (Imahoriand Uchida., J. Biochem 121:179-188, 1997). GSK3β preferentially labelsneurofibrillary tangles and has been shown to be active in pre-tangleneurons in AD brains. GSK3 protein levels are also increased by 50% inbrain tissue from AD patients. Furthermore, GSK3β phosphorylatespyruvate dehydrogenase, a key enzyme in the glycolytic pathway andprevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis ofacetylcholine, a neurotransmitter with cognitive functions. Thus, GSK3βinhibition may have beneficial effects in progression as well as thecognitive deficits associated with Alzheimer's disease and otherabove-referred to diseases.

Chronic and Acute Neurodegenerative Diseases.

Growth factor mediated activation of the PI3K/Akt pathway has been shownto play a key role in neuronal survival. The activation of this pathwayresults in GSK3β inhibition. Recent studies (Bhat et. al., PNAS97:11074-11079 (2000)) indicate that GSK3β activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK3β. Thus GSK3β inhibitors could be useful inattenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressiveepisodes. Lithium has been used to treat BD based on its moodstabilising effects. The disadvantage of lithium is the narrowtherapeutic window and the danger of overdosing that can lead to lithiumintoxication. The recent discovery that lithium inhibits GSK3 attherapeutic concentrations has raised the possibility that this enzymerepresents a key target of lithium's action in the brain (Stambolic etal., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459,1996). Inhibition of GSK3β may therefore be of therapeutic relevance inthe treatment of BD as well as in AD patients that have affectivedisorders.

Schizophrenia

GSK3 is involved in signal transduction cascades of multiple cellularprocesses, particularly during neural development. Kozlovsky et al (Am JPsychiatry 2000 May; 157(5):831-3) found that GSK3β levels were 41%lower in the schizophrenic patients than in comparison subjects. Thisstudy indicates that schizophrenia involves neurodevelopmental pathologyand that abnormal GSK3 regulation could play a role in schizophrenia.Furthermore, reduced β-catenin levels have been reported in patientsexhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383(1998)).

Diabetes

Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et al., Diabetes 2000February; 49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefore be of therapeutic relevance inthe treatment of Type I and Type II diabetes and diabetic neuropathy.

Hair Loss

GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector ofthe pathway for keratonin synthesis. β-catenin stabilisation may be leadto increase hair development. Mice expressing a stabilised β-catenin bymutation of sites phosphorylated by GSK3 undergo a process resembling denovo hair morphogenesis (Gat et al., Cell 1998 Nov. 25; 95 (5):605-14)).The new follicles formed sebaceous glands and dermal papilla, normallyestablished only in embryogenesis. Thus GSK3 inhibition may offertreatment for baldness.

Oral Contraceptives

Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reportedthat GSK3 is high in motile versus immotile sperm. Immunocytochemistryrevealed that GSK3 is present in the flagellum and the anterior portionof the sperm head. These data suggest that GSK3 could be a key elementunderlying motility initiation in the epididymis and regulation ofmature sperm function. Inhibitors of GSK3 could be useful ascontraceptives for males.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide compounds having aninhibiting effect on GSK3 as well as having a good bioavailability.

Accordingly, the present invention provides compounds of formula Ia andIb:

wherein:P represents a 5- or 6-membered heteroaromatic ring containing one ortwo heteroatoms selected independently from N, O and S of which at leastone atom is nitrogen;R¹ is hydrogen;R² and R³ are independently selected from halogen, nitro, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl, CHO, C₀₋₆alkylOR⁴, OC₁₋₆alkylOR⁴, C₀₋₆alkylSR⁴,OC₁₋₆alkylSR⁴, (CO)R⁴, (CO)OR⁴, O(CO)R⁴, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,OC₁₋₆alkylcyano, C₀₋₆alkylcyano, C₁₋₆alkylCO₂R⁴, OC₁₋₆alkylCO₂R⁴,O(CO)OR⁴, OC₁₋₆alkylCOR⁴, C₁₋₆alkylCOR⁴, NR⁴OR⁵, C₀₋₆alkylNR⁴R⁵,OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylCONR⁴R⁵, OC₁₋₆alkylCONR⁴R⁵,OC₁₋₆alkylNR⁴(CO)R⁵, C₀₋₆alkylNR⁴(CO)R⁵, C₀₋₆alkylNR⁴(CO)NR⁴R⁵,O(CO)NR⁴R⁵, NR⁴(CO)OR⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵, OC₁₋₆alkyl(SO₂)NR⁴R⁵,C₀₋₆alkylNR⁴(SO₂)R⁵, OC₁₋₆alkylNR⁴(SO₂)R⁵, C₀₋₆alkyl(SO)NR⁴R⁵,OC₁₋₆alkyl(SO)NR⁴R⁵, SO₃R⁴, C₀₋₆alkylNR⁴(SO₂)NR⁴R⁵, C₀₋₆alkylNR⁴(SO)R⁵,OC₀₋₆alkylNR⁴(SO)R⁵, OC₀₋₆alkylSO₂R⁴, C₀₋₆alkylSO₂R⁴, C₀₋₆alkylSOR⁴,OC₁₋₆alkylSOR⁴ and a group X¹R⁶, wherein X¹ is a direct bond, O,CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹ or NR¹²R¹³; and wherein R⁶ is linked to

R⁸, R¹⁰, R¹¹ and R¹³;

R⁷, R⁹ and R¹² each independently are hydrogen or C₁₋₆alkyl;R⁸, R¹⁰, R¹¹ and R¹³ are C₁₋₆alkyl;R⁶ is phenyl or a 5-, 6- or 7-membered heterocyclic group containing oneor two heteroatoms, selected independently from N, O and S, whichheterocyclic group may be saturated or unsaturated or said phenyl or 5-,6- or 7-membered heterocyclic group may optionally be fused with a 5- or6-membered saturated or unsaturated ring containing atoms selectedindependently from C, N, O and S and which phenyl or heterocyclic groupmay be substituted with one or two substituents selected from W;m is 0, 1, 2, 3 or 4;n is 0, 1, 2, 3 or 4;R⁴ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl,C₁₋₆alkylNR¹⁴R¹⁵ and a 5- or 6-membered heterocyclic group containingone or two heteroatoms, selected independently from N, O and S, whereinsaid heterocyclic group may optionally be substituted by a group Y;R⁵ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl andC₁₋₆alkylNR¹⁴R¹⁵ and; wherein R⁴ and R⁵ may together form a 4-, 5-, 6-or 7-membered heterocyclic group containing one or more heteroatomsselected independently from N, O and S, wherein said heterocyclic groupmay optionally be substituted is by a group Y; and wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl,C₀₋₆alkylaryl; and C₀₋₆alkylheteroaryl defined under R² to R⁵ may besubstituted by one or more group Z;R¹⁴ and R¹⁵ are independently selected from hydrogen, C₁₋₆alkyl andC₀₋₆alkylC₃₋₆cycloalkyl and wherein R¹⁴ and R¹⁵ may together form a 5-or 6-membered heterocyclic group containing one or more heteroatoms,selected independently from N, O and S, wherein said heterocyclic groupmay optionally be substituted by a group Y;W and Z are independently selected from oxo, halogen, nitro, CN, OR¹⁶,C₁₋₆alkyl, C₀₋₆alkylaryl, C₀₋₆alkylC₃₋₆cycloalkyl, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, OC₁₋₆alkylNR¹⁶R¹⁷, NR¹⁶R¹⁷, CONR¹⁶R¹⁷NR¹⁶(CO)R¹⁷,O(CO)C₁₋₆alkyl, (CO)OC₁₋₆alkyl, COR¹⁶, (SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶,(CO)C₁₋₆alkylNR¹⁶R¹⁷, (SO₂)C₁₋₆alkylNR¹⁶R¹⁷, a 5- or 6-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, phenyl and heteroaryl, which heterocyclicgroup, phenyl or heteroaryl may optionally be substituted by a group Y;Y is selected from oxo, halogen, nitro, CN, OR¹⁶, C₁₋₆alkyl,C₀₋₆alkylaryl, C₀₋₆alkylC₃₋₆cycloalkyl, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,OC₁₋₆alkylNR¹⁶R¹⁷, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶(CO)R¹⁷, O(CO)C₁₋₆alkyl,(CO)OC₁₋₆alkyl, COR¹⁶, (SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶, (CO)C₁₋₆alkylNR¹⁶R⁷¹(SO₂)C₁₋₁₆alkylNR¹⁶R¹⁷, phenyl, C₀₋₆alkylaryl and heteroaryl wherein thephenyl, C₀₋₆alkylaryl and heteroaryl group may be optionally substitutedwith halogen, nitro, CN, OR¹⁶, C₁₋₆alkyl, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy and trifluoromethoxy;R¹⁶ and R¹⁷ are independently selected from hydrogen and C₁₋₆alkyl andwherein R¹⁶, and R¹⁷ may together form a 5- or 6-membered heterocyclicgroup containing one or more heteroatoms, selected independently from N,O and S;as a free base or a pharmaceutically acceptable salt thereof.

In one aspect of the invention there is provided compounds of Formula Iaand Ib wherein P is a 6-membered heteroaromatic ring containing one ortwo nitrogen atoms.

In a first embodiment of this aspect of the invention there is providedcompounds of Formula Ia and Ib, wherein P is pyridine.

In another embodiment of this aspect of the invention there is providedcompounds of is Formula Ia and Ib, wherein P is pyrimidine.

In another aspect of the invention there is provided compounds ofFormula Ia.

In yet another aspect of the invention there is provided compounds ofFormula Ia and Ib wherein R² and R³ are independently selected from:halogen, nitro, C₀₋₆alkylheteroaryl, trifluoromethyl, C₀₋₆alkylcyano,C₀₋₆alkylNR⁴R⁵, C₀₋₆alkylCONR⁴R⁵, OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵,and a group X¹R⁶, wherein X¹ is a direct bond; R⁶ is a 5-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, and which heterocyclic group may besubstituted with one or two substituents W, preferably C₁₋₆alkyl; m is0, 1, 2; and n is 1 or 2.

In yet another aspect of the invention there is provided compounds ofFormula Ia and Ib wherein R⁴ is independently selected from hydrogen,C₁₋₆alkyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl,C₁₋₆alkylNR¹⁴R¹⁵ and a 5- or 6-membered heterocyclic group containingone or two heteroatoms, selected independently from N, O and S, whereinsaid heterocyclic group may optionally be substituted by a group Y; R⁵is selected from hydrogen, C₁₋₆alkyl; wherein R⁴ and R⁵ may togetherform a 4-, 5-, 6- or 7-membered heterocyclic group containing one ormore heteroatoms selected independently from N, O and S, wherein saidheterocyclic group may optionally be substituted by a group Y; andwherein any C₁₋₆alkyl, C₀₋₆alkylaryl defined under R² to R⁵ may besubstituted by one or more group Z; R¹⁴ and R¹⁵ are independentlyC₁₋₆alkyl and wherein R¹⁴ and R¹⁵ may together form a 5- or 6-memberedheterocyclic group containing one or more heteroatoms, selectedindependently from N, O and S; Z is independently selected from,halogen, C₁₋₆alkyl, CN, NR¹⁶R¹⁷; Y is selected from C₁₋₆alkyl,C₀₋₆alkylaryl, NR¹⁶R¹⁷, phenyl, wherein the phenyl may be optionallysubstituted with nitro and trifluoromethyl; R¹⁶ and R¹⁷ are C₁₋₆alkyland wherein R¹⁶ and R¹⁷ may together form a 5- or 6-memberedheterocyclic group containing one or more heteroatoms, selectedindependently from N, O and S.

In yet another aspect of the invention there is provided compounds ofFormula Ia and Ib wherein P is pyridine; R¹ is hydrogen; R² is CN; R³ isC₀₋₆alkylNR⁴R⁵; wherein R⁴ and R⁵ may together form a 4-, 5-, 6- or7-membered heterocyclic group containing one or more heteroatomsselected independently from N, O and S.

Yet another aspect of the invention relates to compounds selected from:

-   2-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]isonicotinamide;-   2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;-   2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbonitrile;-   2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide    hydrochloride;-   2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide    hydrochloride;-   2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;-   2-Hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;-   2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;-   2-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;-   3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile;-   2-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}methyl)pyridin-2-yl]-1H-indole-5-carbonitrile;-   3-(5-{[(2-Cyanoethyl)(ethyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;-   3-(5-{[(4-Chlorobenzyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;-   3-(5-{[(2-Furylmethyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;-   2-Hydroxy-3-(5-{[methyl(phenyl)amino]methyl}pyridin-2-yl)-1H-indole-5-carbonitrile;-   2-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;-   3-(5-{[Cyclohexyl(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;-   2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;-   3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol    hydrochloride;-   6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol    hydrochloride;-   3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;-   6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol    hydrochloride;-   2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile    hydrochloride;-   5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol    hydrochloride;-   5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol    hydrochloride;-   3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonitrile    hydrochloride;-   3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-(5-{[4-(3-methylbutyl)piperazin-1-yl]sulfonyl}pyridin-2-yl)-1H-indole-5-carbonitrile    hydrochloride;-   2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile    hydrochloride;-   3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile    hydrochloride;-   3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol;-   3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol    hydrochloride;-   5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol    hydrochloride;-   3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol    hydrochloride;-   3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-ol    hydrochloride;-   2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carbonitrile    hydrochloride;-   N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinamide    hydrochloride;-   6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide    hydrochloride;-   6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamide    hydrochloride;-   5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-2-ol    hydrochloride;-   3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-indol-2-ol    hydrochloride;-   N-[2-(Dimethylamino)-1-methylethyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinamide    hydrochloride;-   6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrollindin-1-ylethyl)nicotinamide    fumarate;-   3-{5-[(4-Methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol    fumarate;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)nicotinamide    fumarate;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide    hydrochloride;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide    fumarate;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide    fumarate;-   6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide    fumarate;-   2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile    fumarate;-   2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitrile;-   3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indol-2-ol    hydrochloride;-   3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-thiazol-4-yl)-1H-indol-2-ol    fumarate;-   3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-oxazol-5-yl)-1H-indol-2-ol;-   3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol    hydrochloride.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₀₋₆’ means a carbon group having 0, 1, 2, 3, 4, 5 or 6carbon atoms.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butis not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl ori-hexyl, t-hexyl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted, saturated cyclic hydrocarbon ringsystem. The term “C₃₋₆cycloalkyl” may be, but is not limited to,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term “alkylaryl”,includes both substituted and unsubstituted alkylaryl groups, which maybe substituted on the alkyl and/or the aryl and may be, but are notlimited to, C₁₋₆alkylaryl, benzyl or ethylphenyl.

In this specification, unless stated otherwise, the term “heteroaryl”may be a monocyclic heteroaromatic, or a bicyclic fused-ringheteroaromatic group. Examples of said heteroaryl include, but are notlimited to, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl,benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl andtriazolyl.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. The term C₂-C₆ alkenyl having 2 to 6 carbonatoms and one or two double bonds, and may be, but is not limited to,vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl,pentenyl, i-pentenyl or hexenyl.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups but referencesto individual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. The term C₂-C₆ alkynyl having 2 to 6 carbonatoms and one or two triple bonds, and may be, but is not limited to,etynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl.

In this specification, unless stated otherwise, the term “5- or6-membered heteroaromatic ring containing one or two heteroatomsselected independently from N, O and S of which at least one atom isselected from nitrogen” includes, but is not limited to, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, imidazolyl.

In this specification, unless stated otherwise, the terms “5- or6-membered heterocyclic group containing one or more heteroatoms,selected independently from N, O and S” or “5-, 6- or 7-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, which heterocyclic group may be saturatedor unsaturated” or “4-, 5-, 6- or 7-membered heterocyclic groupcontaining one or more heteroatoms selected independently from N, O andS” may be, but are not limited to, azepanyl, azitidinyl, imidazolidinyl,imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl,thienyl, imidazolyl.

In this specification, unless stated otherwise, the term “5- or6-membered saturated or unsaturated ring containing atoms selectedindependently from C, N, O and S”, includes both aromatic,heteroaromatic rings and heterocyclic rings that are saturated orunsaturated. Examples of such heterocyclic rings may be, but are notlimited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl,thienyl, imidazolyl, imidazolidinyl, imidazolinyl, morpholinyl,piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl,pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl,cyclohexyl or cyclopentyl.

In this specification, unless stated otherwise, the term “6-memberedheteroaromatic ring containing one or two nitrogen atoms” includes, butis not limited to, pyrazinyl, pyridazinyl, pyridyl or pyrimidyl.

In this specification, unless stated otherwise, the term “5-memberedheterocyclic group containing one or two heteroatoms atoms, selectedindependently from N, O and S” includes, but is not limited to,pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thienyl, furyl, imidazolyl,isothiazolyl or isoxazolyl.

In the case where a subscript is the integer 0 (zero) the group to whichthe subscript refers to, indicates that the group is absent, i.e. thereis a direct bond between the groups.

In this specification, unless stated otherwise, the term halogen may befluorine, chlorine, bromine or iodine.

The present invention relates to the use of compounds of formula Ia andIb as hereinbefore defined as well as to the salts thereof. Salts foruse in pharmaceutical compositions will be pharmaceutically acceptablesalts, but other salts may be useful in the production of the compoundsof formula Ia and Ib.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable salts of the compounds of this invention.Pharmaceutically acceptable salts include, but are not limited tohydrochloride, and fumarate. These salts are readily prepared by methodsknown in the art.

Some compounds of formula Ia and Ib may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomeric and geometric isomers.

Within the present invention it is to be understood that a compound offormula Ia or a salt thereof may exhibit the phenomenon of tautomerismas shown in FIG. 1. It is to be understood that the inventionencompasses any tautomeric form of compounds of formula Ia and is not tobe limited merely to any one tautomeric form utilized within the formuladrawings:

wherein P, R¹, R², R³, m and n are as defined above.

An object of the invention is to provide compounds of formula Ia or Ibfor therapeutic use, especially compounds that are useful for theprevention and/or treatment of conditions associated with glycogensynthase kinase-3 (GSK3) in mammals including man. Particularly,compounds of formula Ia or Ib exhibiting a selective affinity for GSK-3.

Pharmaceutical Compositions

According to one aspect of the present invention there is provided apharmaceutical composition comprising a compound of formula Ia or Ib, asa free base or a pharmaceutically acceptable salt thereof, for use inthe prevention and/or treatment of conditions associated with glycogensynthase kinase-3.

The composition may be in a form suitable for oral administration, forexample as a tablet, for parenteral injection as a sterile solution orsuspension. In general the above compositions may be prepared in aconventional manner using pharmaceutically carriers or diluents.Suitable daily doses of the compounds of formula Ia or Ib in thetreatment of a mammal, including man, are approximately 0.01 to 250mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kgbodyweight at parenteral administration. The typical daily dose of theactive ingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

A compound of formula Ia or Ib, or a pharmaceutically acceptable saltthereof, can be used on its own but will usually be administered in theform of a pharmaceutical composition in which the formula Ia or Ibcompound/salt (active ingredient) is in association with apharmaceutically acceptable diluent or carrier. Dependent on the mode ofadministration, the pharmaceutical composition may comprise from 0.05 to99% w (percent by weight), for example from 0.10 to 50% w, of activeingredient, all percentages by weight being based on total composition.

A diluent or carrier includes water, aqueous polyethylene glycol,magnesium carbonate, magnesium stearate, talc, a sugar (such aslactose), pectin, dextrin, starch, tragacanth, microcrystallinecellulose, methylcellulose, sodium carboxymethyl cellulose or cocoabutter.

A composition of the invention can be in tablet or injectable form. Thetablet may additionally comprise a disintegrant and/or may be coated(for example with an enteric coating or coated with a coating agent suchas hydroxypropyl methylcellulose).

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula I, or a pharmaceutically acceptable salt thereof, ahereinbefore defined, with a pharmaceutically acceptable diluent orcarrier.

An example of a pharmaceutical composition of the invention is aninjectable solution containing a compound of the invention, or apharmaceutically acceptable salt thereof, as hereinbefore defined, andsterile water, and, if necessary, either sodium hydroxide orhydrochloric acid to bring the pH of the final composition to about pH5, and optionally a surfactant to aid dissolution.

Liquid solution comprising a compound of formula Ia or Ib, or a saltthereof, dissolved in water.

Solution mg/mL Active Compound 5.0% w/v Pure water To 100%

Medical Use

Surprisingly, it has been found that the compounds defined in thepresent invention, as a free base or a pharmaceutically acceptable saltthereof, are well suited for inhibiting glycogen synthase kinase-3(GSK3). Accordingly, the compounds of the present invention are expectedto be useful in the prevention and/or treatment of conditions associatedwith glycogen synthase kinase-3 activity, i.e. the compounds may be usedto produce an inhibitory effect of GSK-3 in mammals, including man, inneed of such prevention and/or treatment.

GSK-3 is highly expressed in the central and peripheral nervous systemand in other tissues. Thus, it is expected that compounds of theinvention are well suited for the prevention and/or treatment ofconditions associated with glycogen synthase kinase-3 in the central andperipheral nervous system. In particular, the compounds of the inventionare expected to be suitable for prevention and/or treatment ofconditions associated with especially, dementia, Alzheimer's Disease,Parkinson's Disease, Frontotemporal dementia Parkinson's Type, Parkinsondementia complex of Guam, HIV dementia, diseases with associatedneurofibrillar tangle pathologies and dementia pugilistica.

Other conditions are selected from the group consisting of amyotrophiclateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, postencephelatic parkinsonism, progressivesupranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, headtrauma and other chronic neurodegenerative diseases, Bipolar Disease,affective disorders, depression, schizophrenia, cognitive disorders,hair loss and contraceptive medication.

Further conditions are selected from the group consisting predementedstates, Mild Cognitive Impairment, Age-Associated Memory Impairment,Age-Related Cognitive Decline, Cognitive Impairement No Dementia, mildcognitive decline, mild neurocognitive decline, Late-Life Forgetfulness,memory impairment and cognitive impairment, vascular dementia, dementiawith Lewy bodies and androgenetic alopecia.

One embodiment of the invention relates to the prevention and/ortreatment of dementia and Alzheimer's Disease.

The dose required for the therapeutic or preventive treatment of aparticular disease will necessarily be varied depending on the hosttreated, the route of administration and the severity of the illnessbeing treated.

The present invention relates also to the use of a compound of formulaIa or Ib as defined hereinbefore, in the manufacture of a medicament forthe prevention and/or treatment of conditions associated with glycogensynthase kinase-3.

In the context of the present specification, the term “therapy” alsoincludes “prevention” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides for a method of treatment and/or preventionof conditions associated with glycogen synthase kinase-3 comprisingadministering to a mammal, including man in need of such treatmentand/or prevention a therapeutically effective amount of a compound offormula Ia or Ib, as hereinbefore defined.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds offormula Ia or Ib as a free base or a pharmaceutically acceptable saltthereof, are also useful as pharmacological tools is in the developmentand standardisation of in vitro and in vivo test systems for theevaluation of the effects of inhibitors of GSK3 related activity inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutics agents.

Methods of Preparation

The present invention also relates to processes for preparing thecompound of formula Ia or Ib. Throughout the following description ofsuch processes it is understood that, where appropriate, suitableprotecting groups will be added to, and subsequently removed from thevarious reactants and intermediates in a manner that will be readilyunderstood by one skilled in the art of organic synthesis. Conventionalprocedures for using such protecting groups as well as examples ofsuitable protecting groups are for example described in “ProtectiveGroups in Organic Synthesis”, T. W. Greene, P. G. M Wutz,Wiley-Interscience, New York, 1999.

Preparation of Intermediates

The process, wherein halo is halogen, R³, R⁴, R⁵, R⁶, X¹, n and m,unless otherwise specified, are as defined hereinbefore, comprises,

(i) halogenation of a compound of formula II,

wherein R² is halogen, to obtain a compound of formula III, wherein halois halogen e.g. bromine, chlorine or iodine, may be performed by anaromatic electrophilic substitution using a suitable halogenation agentsuch as Br₂, Cl₂, I₂, ICl, SO₂Cl₂ or another suitable halogenation agentsuch as N-bromosuccinimid in an appropriate solvent such asacetonitrile, acetic acid, HCl/ethanol or water, with or without asuitable base e.g. an alkali metal acetate such as sodium acetate, at areaction temperature between −20° C. and room temperature.(ii) conversion of a compound of formula IV, wherein halo is a halogen,e.g. bromine or iodine, to obtain a compound of formula V, wherein X¹ isa direct bond and R⁶ is as defined above,

that may be carried out by reaction with a suitable tin reagent such asa trialkyltin-R⁶ reagent e.g. tributyltin-R⁶ in the presence of asuitable catalyst such as bis(triphenylphosphine)palladium(II) chloride,tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) acetate in a suitable solvent suchas tetrahydrofuran, acetonitrile, toluene or N,N-dimethylformamide andat a temperature range between 25° C. and reflux. The reaction may beaided by the presence of tetraethyl ammonium chloride.(iii) reduction of a compound of formula VI to obtain a compound offormula VII,

that may be carried out in a suitable solvent such as toluene,tetrahydrofuran, diethyl ether or a mixture of tetrahydrofuran and analcohol such as methanol or ethanol in the presence of a suitablereducing reagent such as lithium borohydride or sodium borohydride andat a reaction temperature between 0° C. and reflux.(iv) oxidation of a compound of formula VII to obtain a compound offormula VIII,

that may be carried out in a suitable solvent such as chloroform,tetrahydrofuran or pyridine in the presence of a suitable oxidizingreagent such as chromium (VI) oxide or manganese (IV) oxide and at areaction temperature between 0° C. and +100° C.(v) conversion of a compound of formula VIII to obtain a compound offormula IX,

that may be carried out in a suitable solvent such as an alcohol e.g.methanol in the presence of a suitable reagent such as tosylmethylisocyanide and a suitable base such as potassium carbonate or sodiumcarbonate and at a reaction temperature between 0° C. and reflux.(vi) conversion of a compound of formula X to obtain a compound offormula XI,

that may be carried out in a suitable solvent such as carbon disulfidein the presence of suitable reagents such as aluminum trichloride andchloroacetyl chloride and at a reaction temperature between 0° C. andreflux.(vii) Conversion of a compound of formula XI to obtain a compound offormula XII,

that may be carried out in a suitable solvent such as toluene, dioxaneor tetrahydrofuran in the presence of a suitable reagent such asthioformamide and a suitable base such as a trialkylamine e.gtriethylamine, or potassium carbonate and at a reaction temperaturebetween +25° C. and reflux.(viii) conversion of a compound of formula XI to obtain a compound offormula XIII,

that may be carried out in a suitable solvent such as acetic acid in thepresence of a suitable reagent such as thioacetamide and at a reactiontemperature between +25° C. and reflux.(ix) conversion of a compound of formula XIV, wherein halo is halogene.g. fluorine, chlorine or bromine, to a compound of formula XV may becarried out by

activation of the acid function in a compound of formula XIV, witha) a halogenation reagent such as thionyl chloride or oxalyl chloride ina suitable solvent such as methylene chloride, chloroform or toluene orusing the reagent neat and the reaction may occur at a temperaturebetween 0° C. and +80° C., followed by the reaction with the appropriateamine R⁴R⁵NH in a suitable solvent such as methylene chloride,chloroform, toluene or acetonitrile with or without a suitable base suchas an alkali metal, an alkaline earth metal carbonate or hydroxide suchas sodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide or an alkylamine base such astriethylamine and the reaction may occur at a temperature between −20°C. and +80° C., orb) a suitable coupling reagent such as 1,3-diisopropylcarbodiimide,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,1,3-dicyclohexylcarbodiimide,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate,1,1′-carbonyldiimidazole orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate where the reaction may be aided by the addition of1-hydroxybenzotriazole hydrate and in a suitable solvent such asmethylene chloride, N,N-dimethylformamide or tetrahydrofuran and thereaction may occur at a temperature between +20° C. and +130° C.,followed by addition of the appropriate amine R⁴R⁵NH and at a reactiontemperature between +20° C. and +130° C.(x) conversion of a compound of formula XVI, wherein halo is halogene.g. fluorine, chlorine or bromine, to a compound of formula XV may becarried out by

the reaction with the appropriate amine R⁴R⁵NH in a suitable solventsuch as methylene chloride, chloroform, toluene or acetonitrile with orwithout a suitable base such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide or analkylamine base such as triethylamine, the reaction may occur at atemperature between −20° C. and +80° C.(xi) Conversion of a compound of formula XVII, wherein halo is halogene.g. fluorine, chlorine or bromine, to a compound of formula XVIII maybe carried out by

activation of the sulfonic acid function in the compound of formula XVIIwith a suitable halogenating reagent such as thionyl chloride orphosphorus oxychloride in a suitable solvent such as methylene chloride,chloroform, acetonitrile or toluene, and sulfolane may be added as aco-solvent to facilitate the reaction. A catalytic amount ofN,N-dimethylacetamide may speed up the reaction and the reaction mayoccur at a temperature between 0° C. and +120° C., followed by thereaction with the appropriate substituted amine R⁴R⁵NH in a suitablesolvent such as methylene chloride, chloroform, toluene or acetonitrilewith or without a suitable base such as sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide or potassium hydroxide oran alkylamine base such as triethylamine and the reaction may occur at atemperature between −20° C. and +80° C.(xii) conversion of a compound of formula XIX, wherein halo is halogene.g. fluorine, chlorine or bromine and R³ is hydrogen or a halogen e.g.fluorine, chlorine or bromine, to a compound of formula XVIIIa may becarried out by

the reaction with the appropriate amine R⁴R⁵NH in a suitable solventsuch as methylene chloride, chloroform, toluene or acetonitrile with orwithout a suitable base such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide or analkylamine base such as triethylamine and the reaction may occur at atemperature between −20° C. and +80° C.(xiii) reaction of a compound of formula XX, wherein halo is halogen, toa compound of formula XXI may be carried out by

the reaction with an appropriate amine R⁴R⁵NH in a suitable solvent suchas methylene chloride, chloroform, acetonitrile or N,N-dimethylformamidewith or without a suitable base such as sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide or potassium hydroxide oran alkylamine base such as triethylamine and the reaction may occur at atemperature between 0° C. and +120° C.(xiv) reaction of a compound of formula XXII, wherein halo is halogene.g. fluorine chlorine, bromine, to a compound of formula XXIII may becarried out by

the reaction with an appropriate reagent R⁴OH in a suitable solvent suchas acetonitrile, methylene chloride, chloroform, toluene orN,N-dimethylformamide in the presence of a suitable base such as sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide,potassium hydroxide or sodium hydride or an alkylamine base such astriethylamine and the reaction may occur at a temperature between 0° C.and +80° C.(xv) Conversion of a compound of formula XXIV, wherein halo is halogene.g. fluorine, chlorine, bromine, to a compound of formula XXV may becarried out by

reacting a compound of formula XXIV with an appropriate amine R⁴R⁵NH ina suitable solvent such as methylene chloride, chloroform, acetonitrileor N,N-dimethylformamide with or without a suitable base such as sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide or, an alkylamine base such as triethylamine or, amacroporous polystyrene anion-exchange resin such as MP-Carbonate or, across linked polystyrene-co-divinylbenzene such asPS-diisopropylethylamine and the reaction may occur at a temperaturebetween 0° C. and +120° C.(xvi) reacting a compound of formula XXVI, wherein R⁴ is C₁₋₆alkyl andhalo is a halogen, e.g. fluorine, chlorine or bromine, with a compoundof formula C (wherein R² and m are as defined above e.g. compounds offormula III, V, IX, XII or XIII) to form a compound of formula XXVII,

may be carried out in an appropriate solvent such as an ether e.g.tetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such astoluene or a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxideand the reaction may occur at a temperature between +10° C. and +150° C.

The reaction is advantageously effected in the presence of a base. Asuitable base may be an organic amine base such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,tetramethylguanidine or an alkali metal or an alkaline earth metalcarbonate or hydroxide such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide.Alternatively, such a base may be an alkali metal hydride such as sodiumhydride, or an alkali metal or alkaline earth metal amide such as sodiumamide, sodium bis(trimethylsilyl)amide, potassium amide or potassiumbis(trimethylsilyl)amide.

(xvii) reacting a compound of formula XXV, wherein halo is a halogen,e.g. fluorine, chlorine or bromine, with a compound of formula C(wherein R² and m are as defined above e.g. compounds of formula III, V,IX, XII or XIII), to form a compound of formula XXVIII, may be carriedout in an appropriate solvent such as an ether e.g. tetrahydrofuran or1,4-dioxan, an aromatic hydrocarbon solvent such as toluene or a dipolaraprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction mayoccur at a temperature between +10° C. and +150° C.

The reaction is advantageously effected in the presence of a base. Asuitable base may be an organic amine base such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,tetramethylguanidine or an alkali metal or an alkaline earth metalcarbonate or hydroxide such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide.Alternatively, such a base may be an alkali metal hydride such as sodiumhydride, or an alkali metal or alkaline earth metal amide such as sodiumamide, sodium bis(trimethylsilyl)amide, potassium amide or potassiumbis(trimethylsilyl)amide.

Methods of Preparation of End products

Another object of the invention are processes a, b, c, d and e for thepreparation of compounds of general formula Ia and Ib, wherein halo ishalogen, P, R¹, R², R³R⁴, R⁵, m and n, unless otherwise specified, aredefined as hereinbefore, and salts thereof.

These processes comprise;a) reacting a compound of formula B (XV, XVIII, XVIIIa, XXI, XXIII),wherein L¹ is a leaving group such as halogen, e.g. fluorine, chlorineor bromine, with a compound of formula C (e.g. compounds of formula III,V, IX, XII, XIII); wherein R¹, R² and m are as defined as hereinbeforeto form a compound of formula Ia;

The reaction of process a may be carried out in an appropriate solventsuch as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatichydrocarbon solvent such as toluene or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulphoxide and the reaction may occur at a temperaturebetween +10° C. and +150° C.

The reaction is advantageously effected in the presence of a base. Asuitable base may be an organic amine base such as pyridine,2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,tetramethylguanidine or an alkali metal or an alkaline earth metalcarbonate or hydroxide such as sodium carbonate, potassium carbonate,calcium carbonate, sodium hydroxide or potassium hydroxide.Alternatively, such a base may be an alkali metal hydride such as sodiumhydride, or an alkali metal or alkaline earth metal amide such as sodiumamide, sodium bis(trimethylsilyl)amide, potassium amide or potassiumbis(trimethylsilyl)amide.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide such as hydrogen chloride or, acarboxylic acid such as fumaric acid in a suitable solvent such astetrahydrofuran, diethyl ether, methanol, ethanol, chloroform ormethylene chloride or mixtures thereof, the reaction may occur between−30° C. to +50° C.

b) reacting a compound of formula XXV, wherein halo is halogen, e.g.fluorine, chlorine or bromine, with a compound of formula C (e.g.compounds of formula III, V, IX, XII, XIII); wherein R¹, R² and m are asdefined as hereinbefore); to form a compound of formula Ia;

The reaction of process b may be carried out in an appropriate solventsuch as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatichydrocarbon solvent such as toluene, or a dipolar aprotic solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide, the reaction may occurat a temperature between +10° C. and +150° C.

The reaction is advantageously effected in the presence of a base. Sucha base may be an organic amine base such as pyridine, 2,6-lutidine,collidine, 4-dimethylaminopyridine, triethylamine, morpholine,N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidineor an alkali metal or an alkaline earth metal carbonate or hydroxidesuch as sodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide. Alternatively, such a base may be analkali metal hydride such as sodium hydride, an alkali metal or analkaline earth metal amide such as sodium amide, sodiumbis(trimethylsilyl)amide, potassium amide or potassiumbis(trimethylsilyl)amide.

The N-oxide may be removed by using a suitable reagent such asphosphorus trichloride in a suitable solvent such as methylene chloride,chloroform, toluene or ethyl acetate and the reaction may occur at atemperature between 0° C. and +100° C.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide such as hydrogen chloride, or acarboxylic acid such as fumaric acid in a suitable solvent such astetrahydrofuran, diethyl ether, methanol, ethanol, chloroform ormethylene chloride or mixtures thereof, the reaction may occur between−30° C. to +50° C.

c) reacting a compound of formula XXVII, wherein R⁴ is C₁₋₆alkyl, withthe appropriate amine HNR⁴R⁵, to form a compound of formula Ia;

The reaction of process c may be carried out by:i) the reaction of the compound of formula XXVII with the appropriateamine R⁴R⁵NH in a suitable solvent such as benzene, methylene chloride,chloroform, toluene or acetonitrile in the presence of a suitablereagent such as trimethyl aluminum and at a reaction temperature between0° C. and reflux or,ii) the reaction of the compound of formula XXVII with the appropriateamine R⁴R⁵NH neat or in a suitable solvent such as methylene chloride,chloroform, toluene or acetonitrile with or without a suitable base suchas an alkali metal, an alkaline earth metal carbonate or hydroxide suchas sodium carbonate, potassium carbonate, calcium carbonate, sodiumhydroxide or potassium hydroxide or an alkyl aminebase such astriethylamine, the reaction may occur at a temperature between −20° C.and +150° C.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide such as hydrogen chloride, or acarboxylic acid such as fumaric acid in a suitable solvent such astetrahydrofuran, diethyl ether, methanol, ethanol, chloroform ormethylene chloride or mixtures thereof, the reaction may occur between−30° C. to +50° C.

d) reduction of the N-oxide in the compound of formula XXVIII to form acompound of formula Ia;

The N-oxide may be reduced by using a suitable reagent such asphosphorus trichloride in a suitable solvent such as methylene chloride,chloroform, toluene or ethyl acetate and the reaction may occur at atemperature between 0° C. and +100° C.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide such as hydrogen chloride, or acarboxylic acid such as fumaric acid in a suitable solvent such astetrahydrofuran, diethyl ether, methanol, ethanol, chloroform ormethylene chloride or mixtures thereof, the reaction may occur between−30° C. to +50° C.

e) fluorinating a compound of formula Ia to form a compound of formulaIb;

The reaction of process e may be carried out in an appropriate solventsuch as an ether e.g. tetrahydrofuran or 1,4-dioxan or mixtures thereofin the presence of a suitable fluorinating reagent such as1-fluoro-2,4,6-trimethylpyridinium triflate and a suitable base such asn-butyllithium or sodium bis(trimethylsilyl)amide and at a reactiontemperature between −40° C. and +80° C.

When it is desired to obtain the acid salt, the free base may be treatedwith an acid such as a hydrogen halide such as hydrogen chloride, or acarboxylic acid such as fumaric acid in a suitable solvent such astetrahydrofuran, diethyl ether, methanol, ethanol, chloroform ormethylene chloride or mixtures thereof, the reaction may occur between−30° C. to +50° C.

Intermediates

The present invention further relates to new intermediates and the useof these intermediates in the preparation of compounds of formula Ia andIb as defined hereinbefore.

In one aspect of the invention the intermediate is a compound accordingto formula XXV

wherein halo is halogen; R³ is selected from halogen, nitro, C₁₋₆alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylcyano,C₀₋₆alkylCONR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵, C₀₋₆alkylNR⁴R⁵ and a group X¹R⁶,wherein X is a direct bond, O, CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹¹ or NR¹²R¹³;R⁷, R⁹ and R¹² each independently are hydrogen or C₁₋₃alkyl; R⁸, R¹⁰,R¹¹ and R¹³ are C₀₋₄alkyl; R⁶ is phenyl or a 5-, 6- or 7-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, which heterocyclic group may be saturatedor unsaturated or said phenyl or 5-, 6- or 7-membered heterocyclic groupmay optionally be fused with a 5- or 6-membered saturated or unsaturatedring containing atoms selected independently from C, N, O and S andwhich phenyl or heterocyclic group may be substituted with one or twosubstituents selected from W; and R⁶ is linked to R⁸, R¹⁰, R¹¹ and R¹³.

In one embodiment of this aspect there are provided compounds accordingto formula XXV wherein R³ is C₀₋₆alkylNR⁴R⁵; and n is 1.

In another aspect there are provided compounds, said compounds being:

-   1-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazine;-   2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide;-   2-Chloro-5-(pyrrolidin-1-ylmethyl)pyridine 1-oxide;-   1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane;-   2-Chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine    1-oxide;-   1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3-amine;-   2-Chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide;-   1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine;-   1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine;-   3-[[(6-Chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile;-   N-(4-Chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methylamine;-   N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine;-   N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine;-   5-(Azetidin-1-ylmethyl)-2-chloropyridine 1-oxide;-   2-Chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide;-   N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine;-   2-Chloro-5-(piperidin-1-ylmethyl)pyridine 1-oxide;    as a free base or a salt thereof.

In another aspect of the invention the intermediate is a compoundaccording to formula B (XV, XVIII, XVIIIa XXI, XXIII)

wherein P represents a 5- or 6-membered heteroaromatic ring containingone or two heteroatoms selected independently from N, O and S of whichat least one atom is selected from nitrogen and L¹ is a leaving groupsuch as a halogen e.g. fluorine, chlorine or bromine; wherein R³ isselected from halogen, nitro, C₁₋₆alkyl, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylcyano, C₀₋₆alkylCONR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵,C₀₋₆alkylNR⁴R⁵ and a group X¹R⁶, wherein X¹ is a direct bond, O,CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹¹ or NR¹²R¹³; R⁷, R⁹ and R¹² each independentlyare hydrogen or C₁₋₃alkyl; R⁸, R¹⁰, R¹¹ and R¹³ are C₀₋₄alkyl; R⁶ isphenyl or a 5-, 6- or 7-membered heterocyclic group containing one ortwo heteroatoms, selected independently from N, O and S, whichheterocyclic group may be saturated or unsaturated or said phenyl or 5-,6- or 7-membered heterocyclic group may optionally be fused with a 5- or6-membered saturated or unsaturated ring containing atoms selectedindependently from C, N, O and S and which phenyl or heterocyclic groupmay be substituted with one or two substituents selected from W; and R⁶is linked to R⁸, R¹⁰, R¹¹ and R¹³.

In one embodiment of this aspect there are provided compounds accordingto formula B (XV, XVIII, XVIIIa XXI, XXIII) wherein P is a pyridine orpyrimidine ring and L¹ is a leaving group such as a halogen e.g.chlorine; wherein R³ is selected from C₀₋₆alkylCONR⁴R⁵,C₀₋₆alkyl(SO₂)NR⁴R⁵ and C₀₋₆alkylNR⁴R⁵; n is 1.

In another aspect there are provided compounds, said compounds being:

-   2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide;-   1-(2-Chloroisonicotinoyl)-4-methylpiperazine;-   6-Chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide;-   4-{2-[(6-Chloropyrimidin-4-yl)oxy]ethyl}morpholine;-   1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine;-   1-[(6-Chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine;-   1-[(6-Chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine;-   1-[(6-Chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine;-   1-[(5-Bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine;-   6-Chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;-   6-Chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide;-   6-Chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide;-   6-Chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide;-   1-[(6-Chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane;-   4-[(6-Chloropyridin-3-yl)sulfonyl]morpholine;    as a free base or a salt thereof.

In yet another aspect of the invention the intermediate is a compoundaccording to formula C (III, V, IX, XII, XIII)

wherein R¹ is hydrogen; R² is selected from halogen, nitro, C₁₋₆alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylcyano,C₀₋₆alkylCONR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵, C₀₋₆alkylNR⁴R⁵ and a group X¹R⁶,wherein X¹ is a direct bond, O, CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹¹ or NR¹²R¹³;R⁷, R⁹ and R¹² each independently are hydrogen or C₁₋₃alkyl; R⁸, R¹⁰,R¹¹ and R¹³ are C₀₋₄alkyl; R⁶ is phenyl or a 5-, 6- or 7-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, which heterocyclic group may be saturatedor unsaturated or said phenyl or 5-, 6- or 7-membered heterocyclic groupmay optionally be fused with a 5- or 6-membered saturated or unsaturatedring containing atoms selected independently from C, N, O and S andwhich phenyl or heterocyclic group may be substituted with one or twosubstituents selected from W; and R⁶ is linked to R⁸, R¹⁰, R¹¹ and R¹³.

In one embodiment of this aspect there are provided compounds accordingto formula C (III, V, IX, XII, XIII) wherein R¹ is hydrogen; R² isselected from halogen and a group X¹R⁶, wherein X¹ is a direct bond; R⁶is a 5- or 6-membered heterocyclic group containing one or twoheteroatoms, selected independently from N, O and S; m is 1 or 2.

In another aspect there are provided compounds, said compounds being:

-   5,6-Dibromo-1,3-dihydroindol-2-one;-   55-Pyridin-3-yl-1,3-dihydro-2H-indol-2-one;-   5-Thien-2-yl-1,3-dihydro-2H-indol-2-one;-   5-(2-Furyl)-1,3-dihydro-2H-indol-2-one;-   5-(1,3-Oxazol-5-yl)-1,3-dihydro-2H-indol-2-one;-   5-(1,3-Thiazol-4-yl)-1,3-dihydro-2H-indol-2-one;-   5-(2-Methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one;    as a free base or a salt thereof.

In yet another aspect of the invention the intermediate is a compoundaccording to formula XXVII

wherein R¹ is hydrogen; R² is selected from halogen, nitro, C₁₋₆alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylcyano,C₀₋₆alkylCONR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵, C₀₋₆alkylNR⁴R⁵ and a group X¹R⁶,wherein X is a direct bond, O, CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹¹ or NR¹²R¹³;R⁷, R⁹ and R¹² each independently are hydrogen or C₁₋₃alkyl; R⁸, R¹⁰,R¹¹ and R¹³ are C₀₋₄alkyl; R⁶ is phenyl or a 5-, 6- or 7-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, which heterocyclic group may be saturatedor unsaturated or said phenyl or 5-, 6- or 7-membered heterocyclic groupmay optionally be fused with a 5- or 6-membered saturated or unsaturatedring containing atoms selected independently from C, N, O and S andwhich phenyl or heterocyclic group may be substituted with one or twosubstituents selected from W; and R⁶ is linked to R⁸, R¹⁰, R¹¹ and R¹³.

In one embodiment of this aspect there are provided compounds accordingto formula XXVII, wherein R¹ is hydrogen; R² is selected from nitro andcyano; m is 1.

In another aspect there are provided compounds, said compounds being:

-   Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate;-   Ethyl 6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate;    as a free base or a salt thereof.

In yet another aspect of the invention the intermediate is a compoundaccording to formula XXVIII

wherein R¹ is hydrogen; R² is selected from halogen, nitro, C₁₋₆alkyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, OC₁₋₆alkylNR⁴R⁵, C₀₋₆alkylcyano,C₀₋₆alkylCONR⁴R⁵, C₀₋₆alkyl(SO₂)NR⁴R⁵, C₀₋₆alkylNR⁴R⁵ and a group X¹R⁶,wherein X¹ is a direct bond, O, CONR⁷R⁸, SO₂NR⁹R¹⁰, SO₂R¹¹ or NR¹²R¹³;R⁷, R⁹ and R¹² each independently are hydrogen or C₁₋₃alkyl; R⁸, R¹⁰,R¹¹ and R¹³ are C₀₋₄alkyl; R⁶ is phenyl or a 5-, 6- or 7-memberedheterocyclic group containing one or two heteroatoms, selectedindependently from N, O and S, which heterocyclic group may be saturatedor unsaturated or said phenyl or 5-, 6- or 7-membered heterocyclic groupmay optionally be fused with a 5- or 6-membered saturated or unsaturatedring containing atoms selected independently from C, N, O and S andwhich phenyl or heterocyclic group may be substituted with one or twosubstituents selected from W; and R⁶ is linked to R⁸, R¹⁰, R¹¹ and R¹³.

In one embodiment of this aspect there are provided compounds accordingto formula XXVIII, wherein R¹ is hydrogen; R² is a group X¹R⁶, whereinX¹ is a direct bond; R⁶ is a 5- or 6-membered heterocyclic groupcontaining one or two heteroatoms, selected independently from N, O andS; m is 1

In yet another aspect there are provided compounds, said compoundsbeing:

-   3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol;-   3-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol;-   5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-indol-2-ol;    as a free base or a salt thereof.

In yet another aspect there are provided compounds, said compoundsbeing:

-   5-(Hydroxymethyl)-1,3-dihydro-2H-indol-2-one;-   2-Oxoindoline-5-carbaldehyde;-   5-(Chloroacetyl)-1,3-dihydro-2H-indol-2-one;    as a free base or a salt thereof.

A further aspect of the invention relates to use of the compoundsaccording to any one of formulas XXV; B (XV, XVIII, XVIIIa XXI, XXIII);C (III, V, IX, XII, XIII); XXVII; XXVIII; in the preparation of acompound of formula Ia or Ib.

WORKING EXAMPLES

The invention will now be illustrated in the following non-limitingExamples and unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room temperature, i.e. at a temperature in the range of18 to 25° C.;(ii) yields are given for illustration only and are not necessarilythose which can be obtained by diligent process development;preparations were repeated if more material was required;(iii) when given, NMR data is in the form of delta values, given inparts per million (ppm) relative to the solvent or relative totetramethylsilane (TMS) as an internal standard;(iv) chemical symbols have their usual meanings; SI units and symbolsare used;(v) solvent ratios are given in volume:volume (v/v) terms; and(vi) mass spectra: where indicated, ionization was effected by chemicalionization (CI), electron impact (EI), fast atom bombardment (FAB) orelectrospray (ESP) unless otherwise indicated; values for m/z are given;generally, only ions which indicate the parent mass are reported.

Example 1 2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide

To a solution of 2-chloroisonicotinic acid (0.50 g, 3.17 mmol) inN,N-dimethylformamide (20 mL) was added 1,1′-carbonyldiimidazole (0.565g, 3.49 mmol). The solution was heated at 70° C. for 30 min. Thereaction mixture was cooled to room temperature andN,N-dimethylethane-1,2-diamine (0.31 g, 3.49 mmol) was added. Thesolution was stirred at room temperature overnight. The solvent wasevaporated in vacuo and the residue was purified on a silica gel columnusing chloroform/methanol/conc. NH₃(aq), (90:10:1), as the eluent toafford 40 mg (5.7% yield) of the title compound as a colorless oil: ¹HNMR (CDCl₃, 400 MHz) δ 8.51 (d, J=5 Hz, 1H), 7.68 (s, 1H), 7.56 (dd,J=5, 1 Hz, 1H), 6.92-7.08 (br s, 1H), 3.58-3.48 (m, 2H), 2.59-2.52 (m,2H), 2.28 (s, 6H); MS (TSP) m/z 228 (M⁺+1).

Example 2 1-(2-Chloroisonicotinoyl)-4-methylpiperazine

The title compound was prepared as described for Example 1 using2-chloroisonicotinic acid and 1-methylpiperazine. The crude product waspurified on a silica gel column using chloroform/methanol/conc. NH₃(aq),(100:10:1), as the eluent to give the title compound as a colorless oil.Yield: 68%: ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (d, J=5 Hz, 1H), 7.57 (s,1H), 7.43 (dd, J=5, 1 Hz, 1H), 3.66-3.58 (m, 2H), 3.28-3.21 (m, 2H),2.41-2.34 (m, 2H), 2.30-2.24 (m, 2H), 2.20 (s, 3H); MS (TSP) m/z 240(M⁺+1).

Example 3 6-Chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide

To a solution of N,N,′N-trimethylethylenediamine (1.0 g, 10 mmol) andtriethylamine (2.0 g, 20 mmol) in methylene chloride (25 mL) was added6-chloronicotinyl chloride (1.7 g, 10 mmol) in methylene chloride (50mL) at room temperature. After 2 h at room temperature, the solvent wasremoved in vacuo and the residue was partitioned between a 2 M aqueousNaOH solution and methylene chloride. The combined extracts were dried(Na₂SO₄) and the solvent was removed in vacuo to afford 2.6 g of a crudeproduct. The residue was purified on a silica gel column usingacetonitrile/triethylamine, (90:10), as the eluent to afford 2.1 g (87%yield) of the title compound as an bright yellow oil: ¹H NMR (DMSO-d6,400 MHz) δ 8.62 (d, J=2 Hz, 1H), 8.06 (dd, J=8, 2 Hz, 1H), 7.76 (d, J=8Hz, 1H), 3.70 (s, 1H), 3.41 (s, 1H), 3.12 (d, J=19 Hz, 3H), 2.64 (s,1H), 2.51 (s, 1H), 2.37 (s, 3H), 2.13 (s, 3H); MS (TSP) m/z 242 (M⁺+1).

Example 4 4-{2-[(6-Chloropyrimidin-4-yl)oxy]ethyl}morpholine

To a solution of N-(2-hydroxyethyl)morpholine (1.09 g, 8.27 mmol) inN,N-dimethylformamide (5 mL) was added sodium hydride (364 mg, 9.10mmol, 60% dispersion in oil) in portions. The mixture was stirred atroom temperature for 1 h and at 45° C. for 1.5 h. The greenish solutionwas added dropwise over 5 min to a solution of 4,6-dichloropyrimidine(3.0 g, 20.1 mmol) in N,N-dimethylformamide (5 mL). The solvent wasremoved in vacuo, and the residue was partitioned between water andethyl acetate. The organic layer was dried (Na₂SO₄) and the solvent wasremoved in vacuo. The crude product was purified on a silica gel columnusing ethyl acetate as the eluent affording 1.17 g (58% yield) of thetitle compound as a yellow oil: ¹H NMR (CDCl₃, 400 MHz) δ 8.57 (s, 1H),6.80 (s, 1H), 4.53 (t, J=6 Hz, 2H), 3.72 (t, J=5 Hz, 4H), 2.77 (t, J=6Hz, 2H), 2.55 (t, J=4 Hz, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ 170.0, 160.7,158.1, 108.0, 66.9, 64.6, 57.1, 53.9; MS (ESP) m/z 244 (M⁺+1).

Example 5 1-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazine

To a suspension of 2-chloro-5-(chloromethyl)pyridine (971 mg, 5.99 mmol)in acetonitrile (50 mL) was added a solution of N-methylpiperazine (1.20g, 12.0 mmol) in acetonitrile (3 mL) followed by potassium carbonate(0.83 g, 5.99 mmol). The obtained yellow solution was heated is atreflux for 40 min. The mixture was allowed to cool for 10 min and thesolvent was removed in vacuo. The residue was partitioned between water,NaCl (s), and ethyl acetate. The aqueous layer was extracted withanother portion of ethyl acetate. The combined organic layers were dried(Na₂SO₄) and the solvent was removed in vacuo affording 1.0 g (74%yield) of the title compound as a yellow oil: ¹H NMR (CDCl₃, 400 MHz) δ8.31 (d, J=2 Hz, 1H), 7.65 (dd, J=8, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H),3.49 (s, 2H), 2.46 (br s, 8H), 2.28 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ150.2, 150.1, 139.5, 132.8, 124.0, 59.2, 55.0, 53.0, 46.0; MS (ESP) m/z226 (M⁺+1).

Example 6 2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide

A mixture of 2-chloro-5-(chloromethyl)pyridine 1-oxide (1.16 g, 6.52mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16,333), morpholine (1.14 g, 13.0 mmol), and potassium carbonate (0.90 g,6.52 mmol) in acetonitrile (30 mL) was stirred at room temperature for72 h. The solvent was removed in vacuo and the residue was purified on asilica gel column using chloroform/ethanol, (9:1), as the eluentaffording 1.21 g (81% yield) of the title compound as a colorless solid:mp 72-74° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 7.39 (d, J=8 Hz,1H), 7.16 (dd, J=8.2 Hz, 1H), 3.65 (t, J=5 Hz, 4H), 3.40 (s, 2H), 2.40(t, J=4 Hz, 4H); ¹³C NMR (CDCl₃, 100 MHz) δ 140.4 (br), 135.9, 126.6,126.6, 66.8, 59.2, 53.4; MS (ESP) m/z 229 (M⁺+1).

Example 7 6-Chloro-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide

The title compound was prepared as described for Example 3 using2-pyrrolidin-1-yl-ethylamine and 6-chloropyridine-3-sulfonyl chloride(described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21,1746-1750). Purification on a silica gel column using ethylacetate/triethylamine, (9:1), as the eluent gave the title compound.Yield: 58%: ¹H NMR (CDCl₃, 400 MHz) δ 8.79 (d, J=2 Hz, 1H), 8.05 (dd,J=8, 3 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 3.00 (app. t, J=6 Hz, 2H), 2.50(app. t, J=6 Hz, 2H), 2.33 (m, 4H), 1.67 (m, 4H); ¹³C NMR (CDCl₃, 100MHz) δ 155.7, 148.8, 137.8, 136.1, 125.0, 54.1, 53.9, 41.6, 23.9; MS(TSP) m/z 290 (M⁺+1).

Example 8 2-Chloro-5-(pyrrolidin-1-ylmethyl)pyridine 1-oxide

To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (477 mg, 2.68mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16,333) in acetonitrile (10 mL) was added pyrrolidine (381 mg, 5.36 mmol),and the reaction mixture was stirred at room temperature overnight. Thesolvent was evaporated, and the residue was dissolved in 2 M HCl(aq) andwashed with ethyl acetate. The aqueous layer was alkalized to pH 8 withNaHCO₃ (s), and the mixture was extracted four times with ethyl acetate.The combined organic layers were dried (Na₂SO₄), and the solvent wasevaporated to give 0.43 g (75% yield) of the title compound as a redoil: ¹H NMR (CDCl₃, 400 MHz) δ 8.37 (d, J=1 Hz, 1H), 7.44 (d, J=8 Hz,1H), 7.23 (dd, J=8, 2 Hz, 1H), 3.57 (s, 2H), 2.51 (m, 4H), 1.80 (m, 4H);¹³C NMR (CDCl₃, 100 MHz) δ 140.1, 139.9, 137.2, 126.4, 126.4, 56.4,54.0, 23.5; MS (ES) m/z 213 (M⁺+1).

Example 91-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane

To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (940 mg, 5.28mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16,333) in acetonitrile (30 mL) were added N-methylhomopiperazine (1.21 g,10.6 mmol), and K₂CO₃ (730 mg, 5.28 mmol). The reaction mixture wasstirred at room temperature for 3.5 days. The solvent was removed invacuo, and the residue was partitioned between brine and ethyl acetate.The aqueous layer was extracted with another two portions of ethylacetate and one portion of tetrahydrofuran. The combined organic layerswere dried (Na₂SO₄), and evaporated to give 0.86 g (64% yield) of thetitle compound as an orange oil: ¹H NMR (acetone-d6, 400 MHz) δ 8.30(dd, J=2 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.29 (dd, J=8, 2 Hz, 1H), 3.65(s, 2H), 2.74-2.69 (m, 4H), 2.62-2.54 (m, 4H), 2.29 (s, 3H), 1.81-1.75(m, 2H); MS (ES) m/z 256 (M⁺+1).

The following Examples, 10-11, were prepared as described for Example 9:

Example 10 2-Chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine1-oxide

Starting material: 4-(1-pyrrolidinyl)piperidine. Yield: 93%: ¹H NMR(CDCl₃, 400 MHz) δ 8.33 (d, J=1 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.21 (dd,J=8, 2 Hz, 1H), 3.41 (s, 2H), 2.83-2.78 (m, 2H), 2.58-2.53 (m, 4H),2.15-2.00 (m, 3H), 1.88-1.83 (m, 2H), 1.81-1.75 (m, 4H), 1.61-1.53 (m,2H); MS (ES) m/z 296 (M⁺+1).

Example 111-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3-amine

Starting material: 3-(dimethylamino)pyrrolidine. Yield: 67%: ¹H NMR(aceton-d6, 400 MHz) δ 8.28 (d, J=1 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.27(dd, J=8, 2 Hz, 1H), 3.66-3.53 (m, 2H), 2.76-2.63 (m, 2H), 2.58-2.50 (m,1H), 2.43-2.35 (m, 1H), 2.24-2.21 (m, 1H), 2.12 (s, 6H), 1.96-1.89 (m,1H), 1.74-1.64 (m, 1H); MS (ES) m/z 256 (M⁺+1).

Example 12 2-Chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide

To a solution of 2-chloro-5-(chloromethyl)pyridine 1-oxide (222 mg, 1.25mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16,333) in tetrahydrofuran (2 mL) were added a solution of4-methylpiperidine (247 mg, 2.49 mmol) in tetrahydrofuran (1.5 mL), acatalytic amount of potassium iodide, and MP-Carbonate (2.55 mmol/g,1.47 g, 3.74 mmol). The mixture was gently stirred at room temperaturefor one week. The mixture was filtered (20 μm polyethylene filter), andthe beads were washed with several portions of methylene chloride. Thefiltrate was washed with NaHCO₃ (aq. sat.), dried (Na₂SO₄), and thesolvent was evaporated to give a crude product which was purified bycolumn chromatography using chloroform/ethanol, (95:5), as the eluent togive 168 mg (56% yield) of the title compound as a yellow oil: ¹H NMR(CDCl₃, 400 MHz) δ 8.37 (d, J=1 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.20 (dd,J=8, 2 Hz, 1H), 3.41 (s, 2H), 2.80-2.75 (m, 2H), 2.00 (dt, J=12, 2 Hz,2H), 1.63-1.58 (m, 2H), 1.45-1.30 (m, 1H), 1.22 (m, 2H), 0.92 (d, J=6Hz, 3H); MS (ES) m/z 241 (M⁺+1).

Example 13 1-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine

PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was washed withtetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine 1-oxide (100 mg,0.56 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem.1979, 16, 333) was added followed by tetrahydrofuran (1 mL). A solutionof 1-phenylpiperazine (182 mg, 1.12 mmol) in tetrahydrofuran (1 mL) anda catalytic amount of potassium iodide were added, and the mixture wasgently stirred (100 r/min) at room temperature for one week.PS-Isocyanate (1.76 mmol/g, 0.80 g, 1.40 mmol) was washed withtetrahydrofuran and added to the mixture followed by additionaltetrahydrofuran (1 mL). The suspension was gently stirred (100 r/min) atroom temperature for 19 h. The suspension was filtered (20 μmpolyethylene filter), and the resins were washed with methylenechloride, tetrahydrofuran, and ethanol. Volatiles were removed in vacuo,and the residue was suspended in a 1:1-mixture of tetrahydrofuran andethanol (8 mL) followed by the addition of N-ethyl-N,N-diisopropylamine(50 μL, 0.28 mmol). The mixture was added to PS-Thiophenol (1.35 mmol/g,0.21 g, 0.28 mmol), and MP-Carbonate (3.20 mmol/g, 90 mg, 0.28 mmol),both pre-swelled in tetrahydrofuran. The mixture was stirred (100 r/min)at room temperature overnight followed by filtration. The resins werewashed with methylene chloride, tetrahydrofuran, and ethanol, and thefiltrate was concentrated in vacuo to give 141 mg (83% yield) of thetitle compound: ¹H NMR (CDCl₃, 400 MHz) δ 8.42 (s, 1H), 7.45 (d, J=8 Hz,1H), 7.30-7.26 (m, 2H), 7.25-7.21 (m, 1 H), 6.95-6.90 (m, 2H), 6.89-6.85(m, 1H), 3.51 (s, 2H), 3.22-3.18 (m, 4H), 2.65-2.60 (m, 4H); MS (ES) m/z304 (M⁺+1).

The following Examples, 14-19, were prepared as described for Example13:

Example 141-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine

Starting material: 1-[2-nitro-4-(trifluoromethyl)phenyl]piperazine.Yield: 100%: ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (d, J=1 Hz, 1H), 8.06 (d,J=2 Hz, 1H), 7.68 (dd, J=9, 2 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.19 (dd,J=8, 2 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 3.54 (s, 2H), 3.18 (t, J=5 Hz,4H), 2.64 (t, J=5 Hz, 4H); MS (ES) m/z 417 (M⁺+1).

Example 153-[[(6-Chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile

Starting material: 3-(ethylamino)propionitrile. Yield: 82%: ¹H NMR(CDCl₃, 400 MHz) δ 8.35 (d, J=1 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.32 (dd,J=9, 1 Hz, 1H), 3.60 (s, 2H), 2.82 (t, J=7 Hz, 2H), 2.60 (q, J=7 Hz,2H), 2.47 (t, J=7 Hz, 2H), 1.07 (t, J=7 Hz, 3H); MS (ES) m/z 240 (M⁺+1).

Example 16N-(4-Chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methylamine

Starting material: p-chloro-N-methylbenzylamine. Yield: 100%: ¹H NMR(CDCl₃/DMSO-d6, 7:1, 400 MHz) δ 8.39 (s, 1H), 7.46 (dd, J=8, 1 Hz, 1H),7.34-7.26 (m, 4H), 7.24-7.20 (m, 1H), 3.54 (d, J=2 Hz, 2H), 3.45 (s,2H), 2.20 (d, J=2 Hz, 3H); MS (ES) m/z 297 (M⁺+1).

Example 17N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine

Starting material: N-methylfurfurylamine. Yield: 71%: ¹H NMR (CDCl₃, 400MHz) δ 8.37 (d, J=1 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.39 (dd, J=2, 1 Hz,1H), 7.22 (dd, J=8, 2 Hz, 1H), 6.34 (dd, J=3, 2 Hz, 1H), 6.22-6.20 (m,1H), 3.61 (s, 2H), 3.46 (s, 2H), 2.26 (s, 3H); MS (ES) m/z 253 (M⁺+1).

Example 18N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine

Starting material: N-methylaniline. Yield: 100%: ¹H NMR (CDCl₃, 400 MHz)δ 8.26 (d, J=1 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.26-7.20 (m, 2H),7.10-7.06 (m, 1H), 6.81-6.75 (m, 1H), 6.71-6.67 (m, 2H), 4.45 (s, 2H),3.02 (s, 3H); MS (ES) m/z 249 (M⁺+1).

Example 19 5-(Azetidin-1-ylmethyl)-2-chloropyridine 1-oxide

Starting material: azetidine. Yield: 100%: MS (ES) m/z 199 (M⁺+1).

Example 20 2-Chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide

PS-Diisopropylethylamine (3.54 mmol/g, 0.4 g, 1.40 mmol) was washed withtetrahydrofuran and 2-chloro-5-(chloromethyl)pyridine 1-oxide (100 mg,0.56 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem.1979, 16, 333) was added followed by tetrahydrofuran (1 mL). A solutionof 3-methylpiperidine in tetrahydrofuran (1.5 mL) and a catalytic amountof potassium iodide were added, and the mixture was gently stirred (80r/min) at room temperature for 5 days. PS-Isocyanate (1.10 mmol/g, 1.27g, 1.40 mmol) was washed with tetrahydrofuran and added to the mixturefollowed by additional tetrahydrofuran (2 mL). The suspension was gentlystirred (80 r/min) at room temperature overnight.N-Ethyl-N,N-diisopropylamine (50 μL, 0.28 mmol) and MP-Carbonate (2.55mmol/g, 0.66 g, 1.68 mmol) were added, and the contents were mixed andgently stirred for 24 h. The mixture was filtered (20 μm polyethylenefilter), and the resins were washed with methylene chloride. Volatileswere removed in vacuo to give 138 mg (99% yield) of the title compound:MS (ES) m/z 241 (M⁺+1).

The following Examples, 21-22, were prepared as described for Example20:

Example 21N-[(6-Chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine

Starting material: N-methylcyclohexylamine. Yield: 96%: MS (ES) m/z 255(M⁺+1).

Example 22 2-Chloro-5-(piperidin-1-ylmethyl)pyridine 1-oxide

Starting material: piperidine: MS (ES) m/z 227 (M⁺+1)

Example 23 6-Dibromo-1,3-dihydroindol-2-one

6-Bromooxindole (0.168 g, 0.8 mmol) was dissolved in acetic acid (4 mL)and stirred for 5 min at room temperature. N-Bromosuccinimide (0.14 g,0.8 mmol) was added and the yellow reaction mixture was stirred for 3 hat ambient temperature. The mixture was poured onto ice and theresulting precipitate was collected by filtration and dried in vacuo togive 0.192 g (83% yield) of the title compound as a white solid: ¹H NMR(DMSO-d6, 400 MHz) δ 10.61 (s, 1H), 7.60 (s, 1H), 7.14 (s, 1H), 3.52 (s,2H).

Example 24 1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine

To a solution of benzylpiperazine (0.45 mL, 2.59 mmol) in methylenechloride (15 mL), cooled on an ice-bath, was 6-chloropyridine-3-sulfonylchloride (0.50 g, 2.36 mmol; described in: Naegeli, C. et al. Helv.Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10mL) added slowly. The reaction was stirred for 30 min and the formedwhite precipitation was filtered and washed with methylene chloride andwater affording, after drying, 0.68 g (82% yield) of the title compound:¹H NMR (DMSO-d6, 400 MHz) δ 8.70 (d, J=3 Hz, 1H), 8.14 (dd, J=8, 3 Hz,1H), 7.76 (d, J=8 Hz, 1H), 7.50-7.43 (m, 2H), 7.38-7.30 (m, 3H), 4.23(br s, 2H), 3.79-3.63 (m, 2H), 3.45-3.18 (m, 2H), 3.11-2.96 (m, 2H),2.96-2.81 (m, 2H); MS (ES) m/z 352 (M⁺+1).

Example 251-[(6-Chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine

To a solution of 1-(3-methylbutyl)piperazine (0.41 g, 2.60 mmol;described in: Yamane, T. et al. Chem. Pharm. Bull. 1993, 41, 148-155) inmethylene chloride (15 mL) cooled on an ice-bath was6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described in:Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved inmethylene chloride (10 mL) added slowly. The reaction was stirred for 30min and a 5% HCl(aq) solution (30 mL) was added and the phases wereseparated. The aqueous layer was alkalyzed with a saturated aqueousNaHCO₃ solution until pH 9 and the mixture was extracted with methylenechloride. The organic layers were combined, dried (Na₂SO₄) and thesolvent was removed in vacuo affording 650 mg (83% yield) of the titlecompound as a white solid: ¹H NMR (CDCl₃, 400 MHz) δ 8.75 (d, J=2 Hz,1H), 7.97 (dd, J=8, 2 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 3.33-3.05 (m, 4H),2.86-2.29 (m, 6H), 1.66-1.50 (m, 1H), 1.5-1.28 (m, 2H), 0.88 (d, J=7 Hz,6H); MS (ES) m/z 332 (M⁺+1).

Example 26 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine

The title compound was prepared as described for Example 25 usingN-isopropylpiperazine and 6-chloropyridine-3-sulfonyl chloride(described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21,1746-1750). Yield: 89%: ¹H NMR (CDCl₃, 400 MHz) δ 8.73 (d, J=3 Hz, 1H),7.96 (dd, J=8, 3 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 3.12-3.01 (m, 4H),2.76-2.63 (m, 1H), 2.63-2.54 (m, 4H), 0.99 (d, J=7 Hz, 6H); ¹³C NMR(CDCl₃, 100 MHz) δ 156.1, 149.3, 138.2, 131.7, 125.0, 54.8, 48.0, 46.7,18.7; MS (ES) m/z 304 (M⁺+1).

Example 27 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine

The title compound was prepared as described for Example 25 usingN-ethylpiperazine and 6-chloropyridine-3-sulfonyl chloride (describedin: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750). Yield:83%: ¹H NMR (CDCl₃, 400 MHz) δ 8.75 (d, J=3 Hz, 1H), 7.97 (dd, J=8, 3Hz, 1H), 7.50 (d, J=8 Hz, 1H), 3.16-3.06 (m, 4H), 2.60-2.46 (m, 4H),2.42 (q, J=7 Hz, 2H), 1.04 (t, J=7 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ155.8, 148.9, 137.8, 131.3, 124.7, 51.9, 51.6, 46.0, 11.9; MS (ES) m/z290 (M⁺+1).

Example 28 1-[(5-Bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine

The title compound was prepared as described for Example 3 using1-methylpiperazine and 5-bromo-6-chloropyridine-3-sulfonyl chloride.Yield: 91%: ¹H NMR (CDCl₃, 400 MHz) δ 8.59 (d, J=2 Hz, 1H), 7.67 (d, J=2Hz, 1H), 3.08-3.01 (m, 4H), 2.43 (t, J=5 Hz, 4H), 2.22 (s, 3H); ¹³C NMR(CDCl₃, 100 MHz) δ 155.5, 146.8, 141.2, 132.7, 121.4, 54.2, 46.3, 46.1.

Example 296-Chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide

To a solution of 6-chloropyridine-3-sulfonylchloride (636 mg, 3 mmol;described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750)in methylene chloride (10 mL) was addedmethyl-(2-pyrrolidin-1-ylethyl)amine (384 mg, 3 mmol; described in: J.Amer. Chem. Soc. 1955, 77, 3632-3634) dissolved in methylene chloride(10 mL) dropwise. The reaction mixture was stirred over night at roomtemperature followed by the extraction with aqueous HCl (3%). The acidicwater layer was alkalized with an aqueous saturated solution of NaHCO₃and extracted with methylene chloride. The organic phase was dried(Na₂SO₄) and evaporated in vacuo to give 0.75 gram (80% yield) of thetitle compound: MS (ES) m/z 304 (M⁺+1).

Example 30 6-Chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide

The title compound was prepared as described for Example 29 using6-chloropyridine-3-sulfonylchloride and N,N-dimethylethane-1,2-diamine.Yield: 72%: MS (ES) m/z 264 (M⁺+1).

Example 316-Chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide

To a solution of N′-ethyl-N,N-dimethylethane-1,2-diamine (0.62 mL, 4.4mmol) in methylene chloride (10 mL) was added6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in:Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved inmethylene chloride (10 mL) dropwise. The reaction mixture was stirredfor 30 min at room temperature followed by the extraction with aqueousHCl (5%). The acidic water layer was alkalized with an aqueous saturatedsolution of NaHCO₃ and extracted with methylene chloride. The organicphase was dried (Na₂SO₄) and evaporated in vacuo to give 0.7 gram (60%yield) of the title compound: MS (ES) m/z 292 (M⁺+1).

Example 326-Chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide

The title compound was prepared as described for Example 31 using(1-ethylpyrrolidin-2-yl)methylamine. Yield: 58%: MS (ES) m/z 304 (M⁺+1).

Example 33 1-[(6-Chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane

The title compound was prepared as described for Example 31 using1-methylhomopiperazine. Yield: 60%: MS (ES) m/z 290 (M⁺+1).

Example 34 4-[(6-Chloropyridin-3-yl)sulfonyl]morpholine

The title compound was prepared as described for Example 31 usingmorpholine. The crude product was purified on a silica gel column usingheptane/ethyl acetate, (1:1), as the eluent: Yield: 60%: MS (ES) m/z 263(M⁺+1).

Example 35 Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate

To a cooled solution of 5-nitrooxindol (5.27 g, 29.6 mmol) inN,N-dimethylamide (50 mL) was added sodium hydride (1.4 g, 35 mmol)during 5 min at 0° C. After 10 min at 0° C., 6-chloronicotinic acidethyl ester (5.0 g, 26.9 mmol) was added dropwise and the reaction washeated to 135° C. for 45 min. The mixture was diluted with water (200mL) and saturated NH₄Cl(aq) (100 mL). The formed precipitate wasfiltrated and washed with water, methanol, ethyl acetate and diethylether. The residual green yellow solid was dried to give 4.1 g (47%yield) of the title compound: ¹H NMR (DMSO-d6, 300 MHz) δ 14.57 (s, 1H),11.24 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=9 Hz, 1H), 7.92(d, J=8 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz, 1H), 4.31 (q,J=7 Hz, 2H), 1.32 (t, J=7 Hz, 3H).

Example 36 Ethyl 6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate

To a solution of 5-cyanooxindole (360 mg, 2.27 mmol) inN,N-dimethylformamide (5 mL) was added sodium hydride (106 mg, 4.41mmol). The greenish reaction mixture was stirred for 50 min whereafter6-chloronicotinic acid ethyl ester (350 mg, 1.89 mmol) dissolved inN,N-dimethylformamide (5 mL) was added. The reaction mixture was heatedat 110° C. for 30 min and water (50 mL) and saturated NH₄Cl(aq) (20 mL)was added, followed by extraction with ethyl acetate. The phases wereseparated and the organic phase contained the title compound as aprecipitation that was filtered off. The solvent was concentrated invacuo and additional product precipitated that was filtered to give 200mg (34% yield) of the title compound in total: ¹H NMR (DMSO-d6, 300 MHz)δ 14.50 (br s, 1H), 11.00 (s, 1H), 8.73 (s, 1H), 7.95 (s, 2H), 7.80 (s,1H), 7.48 (s, 1H), 6.95 (d, J=7 Hz, 1H), 4.50-4.15 (m, 2H), 1.32 (t, J=7Hz, 3H).

Example 37 5-Pyridin-3-yl-1,3-dihydro-2H-indol-2-one

A mixture of 5-bromooxindole (0.95 g, 4.48 mmol),3-(tri-n-butylstannyl)pyridine (1.65 g, 4.48 mmol), tetraethyl ammoniumchloride (2.23 g, 13.4 mmol) and bis(triphenylphospine palladium (II)chloride (0.16 g, 0.22 mmol) in acetonitrile (20 mL) was heated atreflux over night. After cooling to ambient temperature the mixture wasdiluted with chloroform (100 mL) and a potassium fluoride solution (10%,250 mL) was added. The mixture was filtered through Celite and thelayers were separated. The organic layer was dried (Na₂SO₄) and thesolvent was removed in vacuo. The residue was purified on a silica gelcolumn using chloroform/ethanol, (50:1), as the eluent affording 165 mg(18% yield) of the title compound as a white solid: ¹H NMR (DMSO-d6, 400MHz) δ 9.64 (br s, 1H), 7.97 (d, J=2 Hz, 1H), 7.66 (dd, J=5, 1 Hz, 1H),7.21-7.10 (m, 1H), 6.73 (s, 1H), 6.73-6.65 (m, 1H), 6.65-6.54 (m, 1H),6.08 (d, J=8 Hz, 1H), 2.69 (s, 2H); MS (ES) m/z 211 (M⁺+1).

Example 38 5-Thien-2-yl-1,3-dihydro-2H-indol-2-one

The title compound was prepared as described for Example 37 using5-bromooxindole and tri-n-butyl(2-thienyl)tin: MS (ES) m/z 216 (M⁺+1).

Example 39 5-(2-Furyl)-1,3-dihydro-2H-indol-2-one

The title compound was prepared as described for Example 37 using5-bromooxindole and tri-n-butyl(2-furyl)tin: MS (ES) m/z 200 (M⁺+1).

Example 40 5-(Hydroxymethyl)-1,3-dihydro-2H-indol-2-one

To an ice-cooled mixture of methyl 2-oxoindoline-5-carboxylate (0.5gram, 2.6 mmol) in a tetrahydrofuran/ethanol mixture (15:0.3 mL) wasadded lithium borohydride (115 mg, 5.2 mmol) in one portion. After 30min, another portion of lithium borohydride (100 mg, 4.5 mmol) was addedand the reaction solution was stirred for 4 h at room temperature. Athird portion of lithium borohydride (200 mg, 9.2 mmol) and ethanol (0.3mL) were added and the reaction solution was stirred for 14 h at roomtemperature. The reaction was quenched with water (10 mL) and an aqueoussaturated ammonium chloride solution (30 mL) and extracted with ethylacetate. The combined organic phases were dried (Na₂SO₄) and evaporatedin vacuo. The crude product was purified on a silica gel column usingmethylene chloride/methanol, (10:1) as the eluent to give 140 mg (33%yield) of the title compound: ¹H NMR (DMSO-d6, 300 MHz) δ 10.3 (br s,1H), 7.14 (s, 1H), 7.09 (d, J=8 Hz, 1H), 6.74 (d, J=8 Hz, 1H), 5.03 (t,J=6 Hz, 1H), 4.41 (7, J=6 Hz, 2H), 3.44 (s, 2H).

Example 41 2-Oxoindoline-5-carbaldehyde

Chromium (VI) oxide (240 mg, 2.4 mmol) was added to ice-cooled pyridine(3 mL). To the formed yellow suspension was added additional pyridine (2mL) and 5-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (130 mg, 0.8 mmol)dissolved in pyridine (3 mL). The reaction was quenched after 15 min bythe addition of water (50 mL) and extracted with ethyl acetate. Theorganic phases were dried (Na₂SO₄) and evaporated in vacuo. The crudeproduct was purified on a silica gel column using methylenechloride/methanol, (10:1), as the eluent to give 60 mg (46% yield) ofthe title compound.

Example 42 5-(1,3-Oxazol-5-yl)-1,3-dihydro-2H-indol-2-one

A mixture of 2-oxoindoline-5-carbaldehyde (60 mg, 0.38 mmol),tosylmethyl isocyanide (145 mg, 0.75 mmol) and potassium carbonate (103mg, 0.75 mmol) in methanol (20 mL) was heated at reflux for 2 h. Themixture was concentrated in vacuo and diluted with an aqueous saturatedsolution of sodium hydrogencarbonate and extracted with methylenechloride. The combined organic layers were dried (Na₂SO₄) and evaporatedin vacuo. The crude product was purified on a silica gel column usingheptane/ethyl acetate, (1:4), as the eluent to give 40 mg (53% yield) ofthe title compound: ¹H NMR (DMSO-d6, 300 MHz) δ 10.54 (br s, 1H), 8.36(br s, 1H), 7.64-7.44 (m, 3H), 6.89 (d, J=8 Hz, 1H), 3.54 (br s, 2H).

Example 43 5-(Chloroacetyl)-1,3-dihydro-2H-indol-2-one

To a mixture of aluminum trichloride (17 gram, 128 mmol) andchloroacethyl chloride (3 gram, 2.65 mmol) in carbon disulfide (40 mL)was oxindole (2.73 gram, 20.5 mmol) added and the mixture was stirred atreflux for 3.5 h. The mixture was cooled to room temperature andcarefully quenched with cooled water (50 mL). The quenched reactionmixture was stirred for 2 h and the formed precipitate was filtered andwashed two times with water. The solid was dried to give 2.3 gram (53%yield) of the title compound: ¹H NMR (DMSO-d6, 300 MHz) δ 10.82 (br s,1H), 7.87 (d, J=8 Hz, 1H), 7.82 (s, 1H), 6.92 (d, J=8 Hz, 1H), 5.08 (s,2H), 3.57 (s, 2H).

Example 44 5-(1,3-Thiazol-4-yl)-1,3-dihydro-2H-indol-2-one

A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one (630 mg, 3mmol), thioformamide (30 mL, 30 mmol; described in: J. Med. Chem. 1995,858-868) and triethylamine (0.42 mL, 3 mmol) in dioxane was heated at110° C. for 3 h. Additional thioformamide (10 mL, 10 mmol) was added andthe reaction was stirred at 110° C. for 2 h.

This batch was combined with an new batch starting from 230 mg of5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one and the combined reactionmixtures was concentrated to approximately 10 mL and an aqueoussaturated sodium hydrogencarbonate solution (50 mL) was added and thesolution was extracted with ethyl acetate. The combined organic layerswere dried (Na₂SO₄) and evaporated in vacuo. The crude product waspurified on a silica gel column using heptane/ethyl acetate, (1:2), asthe eluent to give 400 mg (35% yield) of the title compound: ¹H NMR(DMSO-d6, 300 MHz) δ 10.47 (s, 1H), 9.15 (s, 1H), 7.97 (s, 1H), 7.83 (brs, 2H), 6.87 (d, J=8 Hz, 1H), 3.54 (s, 2H); MS (ES) m/z 217 (M⁺+1).

Example 45 5-(2-Methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one

A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one (1.5 g, 7.15mmol) and thioacetamide (540 mg, 7.15 mmol) in acetic acid (18 mL) washeated at 80° C. for 3 h. The mixture was cooled to room temperature andthe formed precipitate was filtered and washed with ethyl acetate twotimes and diethyl ether two times and the solid was dried under vacuo togive 1.5 gram (91% yield) of the title compound: ¹H NMR (DMSO-d6, 300MHz) δ 10.49 (s, 1H), 7.90-7.70 (m, 3H), 6.85-6.75 (m, 1H), 3.55 (s,2H), 2.70 (s, 3H).

Example 463-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol

To a suspension of sodium hydride (0.05 g, 1.2 mmol, 60% dispersion inoil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added asolution of 5-pyridin-3-yl-1,3-dihydro-2H-indol-2-one (0.19 g, 0.90mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 20min under nitrogen atmosphere. 2-Chloro-5-(morpholin-4-ylmethyl)pyridine1-oxide (0.14 g, 0.60 mmol), dissolved in N,N-dimethylformamide (3 mL)was added dropwise and the mixture was stirred at room temperature for 2h and then heated at 130° C. for 1.5 h. The solvent was evaporated invacuo and the residue was partitioned between 2 M HCl and ethyl acetateand the phases were separated. The aqueous layer was alkalized byaddition of NaHCO₃ (s) and extracted with ethyl acetate. The organiclayer was dried (Na₂SO₄) and the solvent was removed in vacuo affording200 mg of the title compound as a yellow solid: MS (ES) m/z 403 (M⁺+1).

Example 473-[5-(Morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol

The title compound was prepared as described for Example 46 using5-thien-2-yl-1,3-dihydro-2H-indol-2-one: MS (ES) m/z 408 (M⁺+1).

Example 485-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-indol-2-ol

The title compound was prepared as described for Example 46 using5-(2-furyl)-1,3-dihydro-2H-indol-2-one: MS (ES) m/z 392 (M⁺+1).

Example 492-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]isonicotinamide

To a suspension of sodium hydride (0.15 g, 3.70 mmol, 60% dispersion inoil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added asolution of 5-cyanooxindole (0.29 g, 1.84 mmol) in N,N-dimethylformamide(4 mL). The mixture was stirred for 30 min under a nitrogen atmosphere.2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide (0.21 g, 0.92 mmol)dissolved in N,N-dimethylformamide (4 mL) was added dropwise and themixture was stirred at room temperature for 30 min and then heated at150° C. for 45 min. The solvent was evaporated in vacuo and the residuewas partitioned between ethyl acetate and water. A 2 M aqueous HClsolution was added until pH 2 and the mixture was extracted with ethylacetate. To the aqueous layer, a 45% aqueous NaOH solution was addeduntil pH 11 and the suspension was extracted with ethyl acetate. Theaqueous layer was concentrated in vacuo and the crude product waspurified by preparative HPLC (column: Xterra, 19×300 mm, eluent: 0.05 MNH₄OAc buffert/acetonitrile, 9:1 to 3:7) to give 15 mg (5% yield) of thetitle compound as a red solid: ¹H NMR (DMSO-d₆, 400 MHz) δ 14.88 (br s,1H), 11.03 (br s, 1H), 9.10 (br s, 1H), 8.28 (d, J=6 Hz, 1H), 8.04-7.96(m, 1H), 7.95-7.83 (m, 1H), 7.42-7.34 (m, 1H), 7.13-7.02 (m, 2H),3.62-3.50 (m, 2H), 2.86-2.69 (m, 2H), 2.58-2.29 (m, 6H); MS (TSP) m/z350 (M⁺+1).

Example 502-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

The reaction was performed as described in Example 49 using5-cyanooxindole and 1-(2-chloroisonicotinoyl)-4-methylpiperazine. Thecrude product was purified on a silica gel column usingchloroform/ethanol/conc. NH₃(aq), (100:10:1), as the eluent. The base(20 mg) was dissolved in chloroform and a solution of HCl in diethylether was added until acidic pH. The formed precipitation was filteredand washed with diethyl ether. Drying in vacuo afforded 10 mg the titlecompound as a red solid. Yield: 2%: ¹H NMR (D₂O, 400 MHz) δ 7.82-7.77(m, 1H), 7.18-7.11 (m, 1H), 7.09-7.05 (m, 1H), 7.04-6.98 (m, 1H),6.78-6.71 (m, 1H), 6.67-6.61 (m, 1H), 4.05-3.94 (m, 1H), 3.93-3.82 (m,1H), 3.67-3.48 (m, 2H), 3.48-3.37 (m, 1H), 3.35-3.04 (m, 3H), 2.92-2.80(m, 3H); MS (TSP) m/s 362 (M⁺+1).

Example 512-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile

A mixture of 5-cyanooxindole (213 mg, 1.35 mmol) and sodium hydride (72mg, 1.80 mmol, 60% dispersion in oil) in N,N-dimethylformamide (4 mL)was stirred at room temperature for 10 min. A solution of1-[(6-chloropyridin-3-yl)carbonyl]-4-methylpiperazine (216 mg, 0.901mmol; described in: Thunus, L. Ann. Pharm. Fr. 1977, 35(5-6), 197-203)in N,N-dimethylformamide (2 mL) was added dropwise. The reaction wasstirred at room temperature for 3 h, then at 50° C. for 2.5 h. Thesolvent was removed in vacuo, and the residue was partitioned betweenchloroform and water. The phases were separated and the pH of the waterphases was adjusted to 8 with a 2 M aqueous solution of HCl. The aqueouslayer was extracted with ethyl acetate and the organic layers were dried(Na₂SO₄), combined, and the solvent was removed in vacuo affording anorange semi-solid. The material was purified on a silica gel columnusing chloroform/methanol, (8:2), as the eluent affording 24 mg (7%yield) of the title compound as a yellow solid: mp decomposes >295° C.;¹H NMR (CDCl₃, 400 MHz) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.74 (dd, J=9, 2Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=9 Hz, 1H), 7.36 (dd, J=8, 1 Hz, 1H),7.06 (d, J=8 Hz, 1H), 3.69 (br s, 4H); 2.48 (br s, 4H), 2.36 (s, 3H); MS(TSP) m/z 362 (M⁺+1).

Example 522-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrilehydrochloride

To a suspension of 5-cyanooxindole (720 mg, 4.55 mmol) inN,N-dimethylformamide (5 mL) was added sodium hydride (248 mg, 6.2 mmol,60% dispersion in oil). After 15 min, was added4-[(6-chloropyridin-3-yl)methyl]morpholine (323 mg, 1.52 mmol; describedin: Maienfisch, P. et al. J. Med. Chem. 2000, 43, 5003) to the solution.The reaction mixture was heated at reflux for 1 h. The solvent wasremoved in vacuo, and the residue was partitioned between ethyl acetateand water. A 2 M aqueous HCl solution was added to the ethyl acetate andwater mixture until slightly acidic pH, and then NaHCO₃ (s) was addeduntil saturation. The mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried (Na₂SO₄) and the solvent wasremoved in vacuo. The crude product was dissolved in a mixture ofmethanol and ethyl acetate and was cooled on ice. A solution of HCl indiethyl ether was added until acidic pH. Approximately half of thesolvent volume was removed in vacuo. The precipitated hydrochloride saltwas filtered, washed with ethyl acetate, and dried in vacuo. The saltwas converted back to the base by partitioning between ethyl acetate andan aqueous saturated NaHCO₃ solution. The obtained material (142 mg) waspurified on a silica gel column using chloroform/ethanol, (9:1), as theeluent affording 34 mg (7% yield) of the title compound as the base as ayellow solid: ¹H NMR (CDCl₃, 400 MHz) δ 14.96 (br s, 1H), 8.83 (br s,1H), 7.79 (dd, J=9, 1 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.50 (d, J=9Hz, 1H), 7.29-7.26 (m, 1H), 7.06 (d, J=8 Hz, 1H), 3.75-3.72 (m, 4H),3.44 (s, 2H), 2.50-2.49 (m, 4H).

The base was dissolved in a mixture of methanol, dichloromethane, andethyl acetate (15 mL total volume) and cooled on ice. A solution of HClin diethyl ether (1 M) was added until acidic pH. Approximately half ofthe solvent volume was removed in vacuo, and ethyl acetate was added.The precipitated hydrochloride salt was filtered, washed with ethylacetate, and dried in vacuo at 40° C. affording 33 mg (87% yield fromthe base) as a yellow solid: ¹H NMR (DMSO-d_(6, 400) MHz) δ 14.75 (br s,1H), 11.36 (br s, 1H), 10.98 (s, 1H), 8.30 (s, 1H), 8.07-8.02 (m, 2H),7.90 (d, J=9 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 4.29(s, 2H), 3.98-3.94 (m, 2H), 3.82-3.75 (m, 2H), 3.37-3.32 (m, 2H),3.11-3.08 (m, 2H); ¹³C NMR (DMSO-d6, 100 MHz) δ 168.9, 148.4, 142.6,139.7, 137.4, 124.8, 124.8, 120.8, 119.4, 118.4, 113.1, 108.9, 101.5,85.6, 63.0, 55.5, 50.2; MS (TSP) m/z 335 (M⁺+1).

Example 532-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbonitrile

To a solution of 5-cyanooxindole (411 mg, 2.60 mmol) inN,N-dimethylformamide (4 mL) was added sodium hydride (181 mg, 4.52mmol, 60% dispersion in oil). After 10 min, a solution of4-{2-[(6-chloropyrimidin-4-yl)oxy]ethyl}morpholine (367 mg, 1.51 mmol)in N,N-dimethylformamide (1.5 mL) was added dropwise. The mixture wasstirred at room temperature for 3 h. The solvent was removed in vacuo,and the residue was suspended in a 2 M aqueous HCl solution and washedtwice with ethyl acetate. The aqueous layer was alkalized to pH 8 byadding a 45% aqueous NaOH solution. The obtained suspension wasextracted twice with ethyl acetate. The combined phases were washed withbrine, dried (Na₂SO₄) and the solvent was removed in vacuo. The crudeproduct was purified on a silica gel column using chloroform/ethanol,(9:1), to chloroform/methanol, (8:2), as the eluent affording 172 mg(31% yield) of the title compound as a yellow solid: ¹H NMR (DMSO-d6,400 MHz) δ 10.89 (br s, 1H), 8.62 (s, 1H), 8.02 (s, 1H), 7.30 (d, J=7Hz, 1H), 6.97 (d, J=8 Hz, 1H), 6.83 (br s, 1H), 4.52 (t, J=5 Hz, 2H),3.60 (t, J=4 Hz, 4H), 2.77 (m, 2H), 2.54 (m, 4H); MS (TSP) m/z 366(M⁺+1).

Example 542-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

A mixture of 5-cyanooxindole (694 mg, 4.39 mmol) and sodium hydride (234mg, 5.85 mmol, 60% dispersion in oil) in N,N-dimethylformamide (2.5 mL)was stirred at room temperature for 15 min. To the greenish solution wasadded a solution of 1-[(6-chloropyridin-3-yl)methyl]-4-methylpiperazine(330 mg, 1.46 mmol) in N,N-dimethylformamide (1.2 mL) and the mixturewas heated at 150° C. for 30 min. The mixture was allowed to cool andthe solvent was removed in vacuo. The residue was suspended in a 2 Maqueous HCl solution and washed twice with ethyl acetate. The aqueouslayer was alkalized with NaHCO₃ (s) until saturation followed by threeextractions with ethyl acetate. The organic layers were combined, dried(Na₂SO₄), and the solvent was removed in vacuo. The obtained materialwas purified twice by column chromatography on silica usingchloroform/methanol/conc. NH₃(aq), (90:10:0.5), as the eluent affording56 mg of an oil. 38 mg of the oil was purified by preparative HPLC(column: Xterra, 19×300 mm, eluent: 0.05 M NH₄OAc buffert/acetonitrile,9:1-3:7) affording 29 mg (6% yield) of the title compound as a yellowsolid: mp decomposes>240° C.; ¹H NMR (CDCl₃, 400 MHz) δ 8.74 (s, 1H),7.78 (d, J=9 Hz, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.50 (d, J=9 Hz, 1H),7.29 (m, 1H), 7.06 (d, J=8 Hz, 1H), 3.44 (s, 2H), 2.52 (br s, 8H), 2.31(s, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 169.1, 149.6, 141.7, 136.1, 134.2,125.4, 124.7, 123.6, 121.0, 119.7, 118.4, 109.3, 103.2, 85.4, 59.0,55.0, 52.9, 45.9.

10 mg of the solid was dissolved in a mixture of ethyl acetate,methylene chloride, and a small volume of methanol (10 mL total volume).The solution was cooled on ice and HCl in diethyl ether (1 M) was addeduntil acidic pH. Approximately ⅔ of the solvent volume was removed invacuo and ethyl acetate was added. The precipitated hydrochloride saltwas filtered, washed with ethyl acetate and dried in vacuo affording 12mg of the title compound as an orange solid: ¹H NMR (D₂O, 400 MHz) δ7.78 (s, 1H), 7.68-7.65 (m, 1H), 7.47 (s, 1H), 7.34-7.31 (m, 1H),7.14-7.11 (m, 1H), 6.93-6.6.90 (m, 1H), 3.62-3.48 (m, 10H), 2.77 (s,3H); MS (TSP) m/z 348 (M⁺+1).

Example 556-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-methylnicotinamidehydrochloride

A mixture of sodium hydride (330 mg, 8.2 mmol, 60% dispersion in oil,pre-washed with hexane) in N,N-dimethylformamide (2 mL) was added to5-cyanooxindole (980 mg, 6.2 mmol) in N,N-dimethylformamide (4 mL). Theformed brown mixture was stirred at room temperature for 20 min and6-chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (500 mg, 2.1mmol) in N,N-dimethylformamide (3 mL) was added. The obtained redsolution was heated at 150° C. for 30 min and was then allowed to reachroom temperature overnight. The solvent was removed in vacuo and theresidue was partitioned between a 2 M aqueous HCl solution and ethylacetate. The mixture was alkalized to pH 8 by adding NaHCO₃ (s) andextracted with ethyl acetate. The combined extracts were dried (Na₂SO₄)and the solvent was removed in vacuo to afford 450 mg of a crudeproduct. The residue was purified on a silica gel column usingchloroform methanol/conc. NH₃(aq), (80:19:1), as the eluent. Fractionscontaining product were collected, evaporated in vacuo and dried at 25°C. in vacuo to afford 70 mg. The residue was purified by preparativeHPLC (column: Xterra, 19×300 mm, eluent: 0.05 M NH₄OAcbuffert/acetonitrile, 9:1-3:7). Fractions containing product werecollected, evaporated in vacuo and dried at 25° C. in vacuo to afford 35mg (4.6% yield) of the title compound as the base: ¹H NMR (D₂O, 400 MHz)δ 7.89 (s, 1H), 7.59 (d, J=9 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=8 Hz,1H), 6.84 (d, J=9 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 3.76 (s, 2H), 3.30 (s,2H), 3.07 (s, 3H), 2.84 (s, 6H).

10 mg of the base was dissolved in diethyl ether and treated with 5 MHCl in diethyl ether. The hydrochloride salt was dried at 25° C. invacuo to afford 6 mg of the title compound as an orange powder: MS (ESP)m/z 364 (M⁺+1).

Example 562-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

The reaction was performed as described in Example 55 using1-(6-chloropyridine-3-sulfonyl)-4-methylpiperazine (described in: ThunusL., Annales Pharmaceutiques Francaises 1977, 35, 197-203). Yield: 9.8%:¹H NMR (D₂O, 400 MHz) δ 8.12 (s, 1H), 7.60 (d, J=10 Hz, 1H), 7.13 (s,1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.73 (dd, J=8, 2Hz, 1H), 3.91 (d, J=13 Hz, 2H), 3.60 (d, J=11 Hz, 2H), 3.24 (app. t,J=11 Hz, 2H), 3.02 (app. t, J=12 Hz, 2H), 2.89 (s, 3H); MS (TSP) m/z 398(M⁺+1).

Example 576-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamideHydrochloride

The reaction was performed as described in Example 55 using6-chloro-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide. Purificationon a silica gel column using chloroform/methanol/conc. NH₃(aq),(80:19:1), as the eluent gave the title compound as the base.

Yields: 9.8%. 15 mg of the base was dissolved in methylenechloride/tetrahydrofuran/methanol (3 is mL total volume) and treatedwith 5 M HCl in diethyl ether. The hydrochloride salt was dried at 40°C. in vacuo to afford 11 mg of the title compound as an orange powder:¹H NMR (D₂O, 400 MHz) δ 7.96 (s, 1H), 7.47 (d, J=9 Hz, 1H), 6.87 (s,1H), 6.74 (d, J=8 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.50 (d, J=8 Hz, 1H),3.61 (m, 2H), 3.25 (m, 4H), 3.02 (m, 2H), 1.97 (m, 4H); MS (TSP) m/z 412(M⁺+1).

Example 582-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile

To a suspension of sodium hydride (105 mg, 2.62 mmol, 60% in oil) inN,N-dimethylformamide (2 mL) was added 5-cyanooxindole (310 mg, 1.96mmol). The mixture was stirred at room temperature for 10 min. To theobtained yellowish solution was added2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (299 mg, 1.31 mmol)and the mixture was heated under nitrogen at 130° C. for 30 min. Thedark reaction mixture was allowed to cool and the solvent was removed invacuo. The residue was partitioned between a 2 M aqueous solution of HCland ethyl acetate. The aqueous layer was carefully saturated with NaHCO₃(s) and extracted twice with ethyl acetate. The two last organic layerswere combined, dried (Na₂SO₄) and the solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (50 mL) and a concentratedsolution of phosphorus trichloride (0.5 mL, 5.7 mmol) in ethyl acetate(3 mL) was added. A yellowish precipitate was formed. The mixture wasstirred at room temperature overnight and then heated at 60° C. for 30min and finally at reflux for 10 min. The mixture was allowed to cooland was then diluted with ethyl acetate and washed with a saturatedaqueous NaHCO₃ solution. The aqueous layer was extracted repeatedly withethyl acetate. The combined organic layers were dried (Na₂SO₄) and thesolvent was removed in vacuo. The residue was purified on a silica gelcolumn using chloroform/ethyl acetate, (9:1), as the eluent affording195 mg (45% yield) of the title compound as a yellow solid: mp 228-230°C.; ¹H NMR (DMSO-d6, 400 MHz) δ 14.79 (br s, 1H), 10.87 (s, 1H), 8.10(s, 1H), 7.91 (s, 1H), 7.84 (d, J=9 Hz, 1H), 7.79 (dd, J=9, 1 Hz, 1H),7.28 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.58 (t, J=4 Hz, 4H), 3.39(s, 2H), 2.38 (br s, 4H); ¹³C NMR (DMSO-d6, 100 MHz) δ 168.6, 148.4,142.0, 136.9, 135.9, 125.2, 124.0, 122.3, 121.0, 118.7, 118.3, 108.7,101.2, 84.4, 66.1, 58.3, 52.8; MS (ESP) m/z 335 (M⁺+1).

Example 592-Hydroxy-3-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrilehydrochloride

To a suspension of sodium hydride (60% in mineral oil, 72 mg, 1.80 mmol)in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (213 mg, 1.35mmol), and the mixture was stirred at ambient temperature for 15 min. Tothe obtained brownish solution was added a solution of2-chloro-5-(pyrrolidin-1-ylmethyl)pyridine 1-oxide (191 mg, 0.90 mmol)in N,N-dimethylformamide (1.5 mL). The obtained red solution was heatedat 125° C. for 20 min, and was then allowed to cool. The mixture wasdissolved in 2 M HCl(aq) and washed with ethyl acetate. The organiclayer was extracted with 2 M HCl(aq). The combined aqueous layers werealkalized to saturation with NaHCO₃ (s), and extracted two times withethyl acetate. The extracts were combined, dried (Na₂SO₄) and thesolvent was removed in vacuo to give 270 mg of a crude product. Thematerial was dissolved in ethyl acetate (15 mL), and a solution ofphosphorus trichloride (0.25 mL, 2.87 mmol) in ethyl acetate (3 mL) wasadded. An orange precipitate was immediately formed. The mixture washeated at reflux for 30 min, and was then allowed to cool. The mixturewas partitioned between ethyl acetate and a saturated aqueous NaHCO₃solution. The aqueous layer was extracted with another two portions ofethyl acetate. The combined organic layers were dried (Na₂SO₄) and thesolvent was evaporated to give a crude product which was purified on asilica gel column using chloroform/methanol/conc. NH₃(aq), (90:10:0.5),as the eluent affording 85 mg (37% yield) of the title compound as thefree base as an orange solid: ¹H NMR (CDCl₃, 400 MHz) δ 14.9 (br s, 1H),9.02 (s, 1H), 7.78 (dd, J=9, 2 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.46(d, J=9 Hz, 1H), 7.25-7.22 (m, 1H), 7.05 (d, J=8 Hz, 1H), 3.56 (s, 2H),2.55-2.51 (m, 4H), 1.83-1.79 (m, 4H); MS (ES) m/z 319 (M⁺+1). The base(65 mg) was dissolved in a mixture of ethyl acetate (20 mL), methylenechloride (10 mL), and methanol (2 mL), and was then cooled on anice-bath. A solution of HCl in diethyl ether (1 M) was added untilacidic pH. About 60% of the solvent volume was evaporated and to theresidual suspension was added ethyl acetate. The obtained orangehydrochloride was filtered, washed with ethyl acetate, and dried invacuo at 40° C. affording 65 mg (95% yield from the base) of the titlecompound as a brownish solid: ¹H NMR (DMSO-d6, 400 MHz) δ 14.70 (br s,1H), 11.00 (br s, 1H), 10.97 (s, 1H), 8.31 (s, 1H), 8.07 (dd, J=9, 1 Hz,1H), 8.02 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.32 (d, J=7 Hz, 1H), 7.02 (d,J=7 Hz, 1H), 4.29 (d, J=6 Hz, 2H), 3.45-3.39 (m, 2H), 3.09-3.02 (m, 2H),2.04-1.98 (m, 2H), 1.92-1.87 (m, 2H).

Example 602-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

To a suspension of sodium hydride (60% in mineral oil, 263 mg, 6.58mmol) in N,N-dimethylformamide (3 mL) was added 5-cyanooxindole (0.78 g,4.94 mmol) in portions. The mixture was stirred at ambient temperaturefor 10 min. To the obtained brownish solution was added a solution of1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-methyl-1,4-diazepane (842 mg,3.29 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture washeated at 130° C. under a nitrogen atmosphere for 30 min. The darkmixture was allowed to cool and the solvent was removed in vacuo. To theresidual oil was added 2 M HCl(aq) and the obtained suspension waswashed twice with ethyl acetate. The aqueous layer was neutralized with45% NaOH and alkalized to saturation with NaHCO₃ (s), and extracted twotimes with ethyl acetate, and once with tetrahydrofuran. The extractswere combined, dried (Na₂SO₄) and the solvent was removed in vacuoaffording 1.0 g of the crude N-oxide: MS (ES) m/z 278 (M⁺+1). Part ofthe material (841 mg, 2.23 mmol) was dissolved in acetonitrile (70 mL)during heating. To the warm solution was added phosphorus trichloride (1mL, 11.1 mmol), dropwise initially and then at a faster rate. Theobtained orange suspension was heated at reflux for 1 h, and was thenallowed to cool. The precipitate was filtered, washed with acetonitrile,and dried in vacuo affording 780 mg of an orange residue. Part of thematerial (240 mg) was dissolved in H₂O, NaHCO₃ (s) was added untilsaturation, and the mixture was extracted three times with ethyl acetateand once with tetrahydrofuran. The combined organic layers were dried(Na₂SO₄ and MgSO₄), and the solvent was evaporated to give 165 mg of anoil which was purified on a silica gel column usingchloroform/methanol/conc. NH₃(aq), (80:20:1), as the eluent to give 84mg of the title compound as the free base as a brownish solid: ¹H NMR(DMSO-d6, 400 MHz) δ 14.70 (br s, 1H), 10.79 (br s, 1H), 8.11 (s, 1H),7.92 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.25 (d, J=7Hz, 1H), 6.98 (d, J=7 Hz, 1H), 3.53 (s, 2H), 2.69-2.57 (m, 8H), 2.30 (s,3H), 1.78-1.70 (m, 2H). The base (66 mg) was converted to thehydrochloride using the method described for Example 59. Yield: 99%(calculated from the base) of the title compound as an orange solid: ¹HNMR (D₂O, 400 MHz) δ 7.91 (s, 1H), 7.65 (dd, J=9, 2 Hz, 1H), 7.01-6.95(m, 3H), 6.74 (d, J=7 Hz, 1H), 4.32 (s, 2H), 3.80-3.54 (m, 8H), 2.97 (s,3H), 2.31 (br s, 2H).

The following Examples, 61-62, were prepared as described for Example60:

Example 612-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

Starting material:2-chloro-5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridine 1-oxide.The product was purified on a silica gel column usingchloroform/methanol/conc. NH₃(aq), (90:10:0.5), as the eluent. Yield:15% of the title compound as the base as an orange solid: ¹H NMR (CDCl₃,400 MHz) δ 8.75 (br s, 1H), 7.76 (dd, J=9, 2 Hz, 1H), 7.69 (s, 1H), 7.64(s, 1H), 7.49 (d, J=9 Hz, 1H), 7.29-7.25 (m, 1H), 7.05 (d, J=8 Hz, 1H),3.41 (s, 2H), 2.88 (d, J=11 Hz, 2H), 2.58 (br s, 4H), 2.11-1.99 (m, 3H),1.90 (d, J=12 Hz, 2H), 1.80 (br s, 4H), 1.65-1.53 (m, 2H); MS (ES) m/z402 (M⁺+1). The base (72 mg) was dissolved in a mixture of ethyl acetate(5 mL), methylene chloride (10 mL), and was then cooled on an ice-bath.A solution of HCl in diethyl ether was (1 M) added until acidic pH. Theobtained orange hydrochloride was filtered, washed with ethyl acetate,and dried in vacuo at room temperature affording 68 mg (80% yield,calculated from the base) of the title compound as an orange solid: ¹HNMR (D₂O, 400 MHz) δ 7.90 (s, 1H), 7.71 (d, J=9 Hz, 1H), 7.25 (s, 1H),7.15 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.00(br s, 2H), 3.55-3.41 (m, 5H), 2.92-2.82 (m, 2H), 2.43 (d, J=13 Hz, 2H),2.09 (br s, 4H), 1.98-1.87 (m, 2H).

Example 623-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile

Starting material:1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N,N-dimethylpyrrolidin-3-amine.The crude product was purified on a silica gel column usingchloroform/methanol/conc. NH₃(aq), (85:15:1), as the eluent. Theobtained material was purified further by preparative HPLC (column:Xterra, C₈, 7 μm, 19×300 mm; eluent: 0.1 M NH₄OAc buffer/acetonitrile,8:2 to 4:6) affording the title compound as an orange solid. Yield: 6%:¹H NMR (CDCl₃, 400 MHz) δ 9.12 (br s, 1H), 7.77 (d, J=9 Hz, 1H), 7.71(s, 1H), 7.63 (s, 1H), 7.49 (d, J=9 Hz, 1H), 7.28-7.24 (m, 1H), 7.06 (d,J=8 Hz, 1H), 3.60-3.48 (m, 2H), 2.95-2.89 (m, 1H), 2.82-2.76 (m, 1H),2.72-2.68 (m, 1H), 2.64-2.58 (m, 1H), 2.53-2.48 (m, 1H), 2.27 (s, 6H),2.09-2.00 (m, 1H), 1.87-1.79 (m, 1H); MS (ES) m/z 362 (M⁺+1).

Example 632-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile

To a suspension of sodium hydride (60% in mineral oil, 54 mg, 1.35 mmol)in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (161 mg, 1.02mmol), and the mixture was stirred at ambient temperature for 10 min. Tothe obtained brownish solution was added a solution of2-chloro-5-[(4-methylpiperidin-1-yl)methyl]pyridine 1-oxide (163 mg,0.677 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture washeated at 130° C. for 25 min, and was then allowed to cool. The solventwas removed in vacuo, and to the residue was added 2 M HCl(aq). Theobtained precipitate was partitioned between a saturated aqueous NaHCO₃solution and ethyl acetate. The aqueous layer was extracted with anothertwo portions of ethyl acetate. The combined organic layers were dried(Na₂SO₄), and the solvent was removed in vacuo affording a crudeproduct. The material was dissolved in ethyl acetate (25 mL), andphosphorus trichloride (0.24 mL, 2.71 mmol) was added. An orangeprecipitate was immediately formed. The mixture was heated at reflux for30 min, and was then allowed to cool. The mixture was partitionedbetween ethyl acetate and a saturated aqueous NaHCO₃ solution. Theaqueous layer was extracted with another portion of ethyl acetate. Thecombined organic layers were dried (Na₂SO₄), and the solvent wasevaporated. The crude product was purified on a silica gel column usingchloroform/methanol, (95:5), as the eluent followed by preparative HPLC(column: Xterra, C₈, 7 μm, 19×300 mm; eluent: 0.1 M NH₄OAcbuffer/acetonitrile, 8:2 to 4:6) affording 4 mg (2% yield) of the titlecompound as an orange solid: ¹H NMR (acetone-d6, 400 MHz) δ 9.88 (br s,1H), 8.11 (d, J=1 Hz, 1H), 7.90 (dd, J=9, 2 Hz, 1H), 7.85 (d, J=9 Hz,1H), 7.82 (d, J=1 Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz,1H), 3.44 (s, 2H), 2.91-2.86 (m, 2H), 2.10-1.98 (m, 2H), 1.65-1.59 (m,2H), 1.40-1.35 (m, 1H), 1.28-1.16 (m, 2H), 0.92 (d, J=7 Hz, 3H); MS (ES)m/z 347 (M⁺+1).

Example 642-Hydroxy-3-{5-[(4-phenylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile

To a suspension of sodium hydride (60% dispersion in mineral oil, 45 mg,1.12 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole(133 mg, 0.84 mmol). The mixture was stirred for 15 min, and asuspension of1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-phenylpiperazine (0.56 mmol)in N,N-dimethylformamide (2.3 mL) was added. The reaction mixture washeated at 130° C. for 10 min and was then allowed to cool to roomtemperature. The dark reaction mixture was acid/base-extracted using anAllex robot. The following steps were included: addition of HCl (aq),washing with ethyl acetate (to remove excess of 5-cyanooxindole),alkalization with (sat) NaHCO₃, and finally repeated extractions withethyl acetate. The combined organic extracts were dried (Na₂SO₄), andthe solvent was removed in vacuo. The residue was dissolved in ethylacetate (10 mL), and phosphorus trichloride (0.2 mL, 2.24 mmol) wasadded. The resulting suspension was stirred at ambient temperature for1.5 h, and then heated at reflux for 30 min. The reaction mixture wasallowed to cool to room temperature. The mixture was washed with asaturated aqueous NaHCO₃ solution using an Allex robot. The aqueouslayer was repeatedly extracted with ethyl acetate. The combined organiclayers were dried (Na₂SO₄), and the solvent was evaporated to give 20 mgof an orange product which was purified on silica usingchloroform/ethanol, (95:5), as the eluent. The obtained material (10 mg)was purified further by preparative HPLC (column: Xterra, C₈, 7 μm,19×300 mm; eluent: 0.1 M NH₄OAc buffer/acetonitrile, 8:2 to 4:6)affording 5 mg (1.1% yield) of the title compound: ¹H NMR (DMSO-d6, 400MHz) δ 14.78 (br s, 1H), 10.86 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H),7.86-7.82 (m, 2H), 7.27 (d, J=8 Hz, 1H), 7.23-7.16 (m, 2H), 7.00 (d, J=8Hz, 1H), 6.93 (d, J=8 Hz, 2H), 6.77 (t, J=7 Hz, 1H), 3.46 (s, 2H),3.16-3.12 (m, 4H), 2.57-2.53 (m, 4H); MS (ES) m/z 410 (M⁺+1).

The following Examples, 65-70, were prepared as described for Example64:

Example 653-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile

Starting material: 5-(azetidin-1-ylmethyl)-2-chloropyridine 1-oxide. Thetitle compound was purified on a silica gel column usingchloroform/methanol/conc. NH₃(aq), (90:10:0.5). Yield: 1%: ¹H NMR(acetone-d6, 400 MHz) δ 9.86 (br s, 1H), 8.10 (s, 1H), 7.86-7.83 (m,2H), 7.81 (d, J=2 Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz,1H), 3.51 (d, J=1 Hz, 2H), 3.22 (t, J=7 Hz, 4H); MS (ES) m/z 305 (M⁺+1).

Example 662-Hydroxy-3-[5-({4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}methyl)pyridin-2-yl]-1H-indole-5-carbonitrile

Starting material:1-[(6-chloro-1-oxidopyridin-3-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine.Yield: 1%: ¹H NMR (DMSO-d6, 400 MHz) δ 14.79 (br s, 1H), 10.85 (s, 1H),8.15-8.12 (m, 2H), 7.90 (s, 1H), 7.87-7.80 (m, 3H), 7.43 (d, J=9 Hz,1H), 7.27 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.47 (s, 2H), 3.17-3.14(m, 4H), 2.55-2.52 (m, 4H); MS (ES) m/z 523 (M⁺+1).

Example 673-(5-{[(2-Cyanoethyl)(ethyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile

Starting material:3-[[(6-chloro-1-oxidopyridin-3-yl)methyl](ethyl)amino]propanenitrile.Yield: 1%: ¹H NMR (DMSO-d6, 400 MHz) δ 14.80 (br s, 1H), 10.84 (s, 1H),8.11 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 1H),7.26 (d, J=8 Hz, 1H), 6.99 (d, J=8 Hz, 1H), 3.52 (s, 2H), 2.73-2.70 (m,2H), 2.69-2.65 (m, 2H), 2.53 (q, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H); MS(ES) m/z 346 (M⁺+1).

Example 683-(5-{[(4-Chlorobenzyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile

Starting material:N-(4-chlorobenzyl)-N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methylamine.Yield: 1%: ¹H NMR (DMSO-d6, 400 MHz) δ 14.79 (br s, 1H), 10.85 (s, 1H),8.15 (s, 1H), 7.90 (s, 1H), 7.85-7.82 (m, 2H), 7.41-7.36 (m, 4H), 7.27(d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 3.52 (s, 2H), 3.44 (s, 2H), 2.11(s, 3H); MS (ES) m/z 401 (M⁺+1).

Example 693-(5-{[(2-Furylmethyl)(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile

Starting material:N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-(2-furylmethyl)-N-methylamine.Yield: 4%: ¹H NMR (DMSO-d6, 400 MHz) δ 14.80 (br s, 1H), 10.86 (s, 1H),8.10 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 1H),7.61 (d, J=1 Hz, 1H), 7.27 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 6.43(dd, J=3, 2 Hz, 1H), 6.34 (d, 3 Hz, 1H), 3.59 (s, 2H), 3.42 (s, 2H),2.15 (s, 3H); MS (ES) m/z 359 (M⁺+1).

Example 702-Hydroxy-3-(5-{[methyl(phenyl)amino]methyl}pyridin-2-yl)-1H-indole-5-carbonitrile

Starting material:N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-methyl-N-phenylamine. Theproduct was purified on a silica gel column usingchloroform/methanol/conc. NH₃(aq), (90:10:0.5), as the eluent. Yield 2%:¹H NMR (DMSO-d6, 400 MHz) δ 10.82 (br s, 1H), 8.06 (s, 1H), 7.91-7.68(m, 3H), 7.26-7.23 (m, 1H), 7.22-7.16 (m, 2H), 7.00-6.96 (m, 1H), 6.80(d, J=8 Hz, 2H), 6.66 (t, J=7 Hz, 1H), 4.49 (s, 2H), 2.98 (s, 3H); MS(ES) m/z 353 (M⁺−1).

Example 712-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile

To a suspension of sodium hydride (60% in mineral oil, 45 mg, 1.12 mmol)in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (133 mg, 0.84mmol), and the mixture was stirred at ambient temperature for 10 min. Tothe obtained brownish solution was added a solution of2-chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide (0.56 mmol)in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at130° C. for 30 min, and was then allowed to cool. To the residue wasadded 2 M HCl(aq) and the obtained suspension was washed with ethylacetate. The aqueous layer was neutralized with 45% NaOH(aq) andalkalized to saturation with NaHCO₃ (s), and extracted two times withethyl acetate. The extracts were combined, dried (MgSO₄) and the solventwas removed in vacuo affording 84 mg of the crude product. The materialwas dissolved in ethyl acetate (10 mL), and to the solution was addedphosphorus trichloride (0.2 mL, 2.24 mmol). The obtained orangesuspension was heated at reflux for 1 h and was then allowed to cool.The precipitate was filtered, washed with ethyl acetate, and dried invacuo affording 70 mg of an orange residue. The material was purified bypreparative HPLC (column: Xterra, C₈, 7 μm, 19×300 mm; eluent: 0.1 MNH₄OAc buffer/acetonitrile, 8:2 to 4:6) affording 15 mg (8% yield) ofthe title compound as an orange solid: ¹H NMR (acetone-d6, 400 MHz) δ9.86 (br s, 1H), 8.11 (s, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 7.84 (d, J=9Hz, 1H), 7.82 (d, J=1 Hz, 1H), 7.26 (dd, J=8, 2 Hz, 1H), 7.11 (d, J=8Hz, 1H), 3.44 (s, 2H), 2.00-1.50 (m, 6H), 0.95-0.81 (m, 4H); MS (ES) m/z347 (M⁺+1).

The following Examples, 72-73, were prepared as described for Example71:

Example 723-(5-{[Cyclohexyl(methyl)amino]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile

Starting material:N-[(6-chloro-1-oxidopyridin-3-yl)methyl]-N-cyclohexyl-N-methylamine.Yield: 3%: ¹H NMR (CDCl₃, 400 MHz) δ 8.64 (br s, 1H), 7.79 (dd, J=9, 2Hz, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.53 (d, J=9 Hz, 1H), 7.30 (dd,J=8, 1 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 3.52 (s, 2H), 2.23 (s, 3H),1.88-1.80 (m, 5H), 1.36-1.02 (m, 6H); MS (ES) m/z 361 (M⁺+1).

Example 732-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile

Starting material: 2-chloro-5-(piperidin-1-ylmethyl)pyridine 1-oxide.Yield: 4%: ¹H NMR (acetone-d₆, 400 MHz) δ 9.85 (br s, 1H), 8.11 (s, 1H),7.91 (dd, J=9, 2 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.82 (d, J=1 Hz, 1H),7.26 (dd, J=8, 2 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 3.43 (s, 2H), 2.47-2.41(m, 4H), 1.61-1.54 (m, 4H), 1.49-1.41 (m, 2H); MS (ES) m/z 333 (M⁺+1).

Example 743-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-olHydrochloride

Sodium hydride (46 mg, 60% dispersion in paraffin) was washed withhexane and dried in vacuo. N,N-Dimethylformamide (3 mL), oxindole (72mg, 0.54 mmol) and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine(100 mg, 0.36 mmol; described in: Thunus L., Annales PharmaceutiquesFrancaises 1977, 35, 197-203) were added to the sodium hydride and thereaction mixture was stirred at room temperature for 5 min. The reactionmixture was then heated for 10 min at 130° C. After cooling to roomtemperature, a saturated aqueous sodium hydrogen carbonate solution wasadded. The mixture was extracted twice with methylene chloride and thecombined organic layers were dried (Na₂SO₄), filtrated and the solventwas removed in vacuo. The residue was purified on a silica gel columnusing a gradient ethyl acetate/methanol, (40:1 to 1:1), as the eluent.The product was dissolved in a mixture of methylene chloride (5 mL) andmethanol (5 mL). Hydrogen chloride (3 mL, 1 M in diethyl ether) wasadded and stirring was continued for 10 min. The precipitate was washedwith diethyl ether and dried in vacuo to give 50 mg (37% yield) of thetitle compound: ¹H NMR (D₂O, 400 MHz) δ 7.95 (m, 1H), 7.45 (d, J=2 Hz,1H), 7.43 (dd, J=9, 2 Hz, 1H), 7.23 (m, 1H), 7.14 (d, J=9 Hz, 1H), 7.00(m, 2H), 3.88 (d, J=14 Hz, 2H), 3.60 (d, J=12 Hz, 2H), 3.23 (m, 2H),2.94 (m, 2H), 2.90 (s, 3H); MS (ES) m/z 373 (M⁺+1).

Example 756-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 74 using6-chlorooxindole. The base was purified on a silica gel column using agradient chloroform/methanol, (100:0 to 4:1), as the eluent. The productwas dissolved in a mixture of chloroform (10 mL) and methanol (10 mL).Hydrogen chloride (3 mL, 1 M in diethyl ether) was added and stirringwas continued for 10 min. The precipitate was washed with diethyl etherand dried in vacuo to give 50 mg (29% yield) of the title compound: ¹HNMR (DMSO-d6, 400 MHz) δ 10.95 (m, 1H), 10.79 (s, 1H), 8.49 (s, 1H),7.68 (m, 1H), 7.64 (m, 1H), 7.55 (d, J=8 Hz, 1H), 6.98 (m, 1H), 6.93 (m,1H), 3.74 (m, 2H), 3.45 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.75 (m,3H); MS (ES) m/z 407 (M⁺+1).

Example 763-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol

Ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (0.327 g, 1.0 mmol)was suspended in benzene (13 mL) followed by the addition of morpholine(0.218 g, 2.5 mmol). The mixture was stirred (N2 atmosphere) for 5 minat 0° C. To this mixture, trimethyl aluminum (2 M solution in hexane, 2mL, 4 mmol) was added via a syringe. After 10 min the temperature wasraised to 70° C. and the reaction mixture was stirred for 20 h thenpoured onto an ice-cold aqueous saturated NaHCO₃ solution and extractedwith chloroform. The combined organic layer was concentrated and thelight brown residue was purified on a silica gel column usingchloroform/methanol/triethylamine, (50:10:1), as eluent to give 0.22 g(60% yield) of the title compound: ¹H NMR (acetone-d6, 400 MHz) δ 8.47(s, 1H), 8.41 (s, H), 8.05 (d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H), 7.90(d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 3.79 (br s, 2H), 3.73 (br s, 4H),2.68 (br s, 4H); MS (EI) m/z 369 (M+1⁺).

Example 776-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-olHydrochloride

To a N,N-dimethylformamide (1.5 mL) suspension of sodium hydride (60%dispersion in oil, 40 mg, 1.0 mmol, pre-washed with hexane) was added6-bromoxindole (0.159 g, 0.75 mmol). The formed mixture was stirred for5 min at room temperature followed by the addition of2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (0.114 g, 0.5 mmol).The resulting reaction mixture was stirred (N₂ atmosphere) for 30 min at120° C. The solvent was evaporated in vacuo and the residual oil waspurified on a silica gel column using chloroform/methanol, (10:1), aseluent affording the N-oxide product. The N-oxide was dissolved inchloroform (3 mL) and phosphorus trichloride (0.412 g, 3.0 mmol) wasadded. The reaction mixture was stirred for 30 min at 60° C. and thencooled to room temperature. The mixture was quenched with methanol andconcentrated. The residue was purified on a silica column using achloroform/methanol gradient, (10:1 to 1:2), as the eluent to give 52 mg(4% yield) of the title compound as the base as brownish solid. The base(30 mg, 0.077 mmol) was dissolved in methylene chloride/methanol, (1:1),and treated with 1 M HCl in diethyl ether at 0° C. The resultingyellowish orange crystals were collected by filtration and washed withdiethyl ether to give 5 mg (15% yield) of the title compound: ¹H NMR(DMSO-d6, 400 MHz) δ 10.61 (s, 1H), 8.59 (br s, 1H), 8.23 (s, 1H), 7.96(s, 1H), 7.70 (s, 1H), 7.54 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 7.05(s, 1H), 4.17 (br s, 2H), 3.85 (br s, 4H), 3.10 (br s, 4H); MS (EI) m/z388 (M), 390 (M⁺+2).

Example 782-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrileHydrochloride

The title compound was prepared as described for Example 77 using6-cyanooxindole. The base was obtained as a yellow solid afterpurification by preparative HPLC (column: Xterra, C₈, 7 μm, 19×300 mm;eluent: 0.1 M NH₄OAc buffer/acetonitrile, 8:2 to 4:6). Yield: 13%. Thebase was transformed to the yellow hydrochloride salt in 33% yield: ¹HNMR (D₂O, 400 MHz) δ 8.21 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.82 (d, J=8Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.29 (s, 1H), 7.28 (d, J=8 Hz, 1H), 3.97(s, 2H), 3.69 (br s, 4H), 2.65 (br s, 4H); MS (EI) m/z 335 (M⁺+1).

Example 795-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-olHydrochloride

To a N,N-dimethylformamide (3.0 mL) suspension of sodium hydride (60%dispersion in oil, is 0.480 g, 12.0 mmol, pre-washed with hexane) wasadded 5-bromooxindole (1.9 g, 9.0 mmol). The mixture was stirred for 10min at 0° C. and for 5 min at room temperature.2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (1.37 g, 6.0 mmol) wasadded and the resulting reaction mixture was stirred (N₂ atmosphere) for50 min at 120° C., then cooled to room temperature. TheN,N-dimethylformamide solution was diluted with an aqueous saturatedNaHCO₃ solution and NaCl (s, 2 g) was added followed by extraction withchloroform and ethyl acetate. The combined organic phases were dried(Na₂SO₄) and concentrated in vacuo. The remaining N,N-dimethylformamidewas removed by co-evaporation with toluene two times. The residual oilwas dissolved in chloroform (10 mL) and phosphorus trichloride (3.0 g,21.8 mmol) was added. The reaction mixture was stirred for 30 min at 60°C. and then cooled to room temperature. The mixture was poured into anaqueous saturated NaHCO₃ solution.

A brown precipitate was formed, which was filtered off, and the filtrate(containing some product) was treated separately (see bellow).

The brown solid was dissolved in methanol (150 mL) and insolublematerials were removed by filtration. This solution was concentrated toa brownish yellow solid, which was suspended in ethyl acetate (15 mL)and stirred overnight at room temperature. The yellow solid wascollected by filtration and dried to afford 1.28 g of the product.

To the NaHCO₃ solution (filtrate, see above), NaCl(s) (2.0 g) was addedfollowed by extractions with chloroform and ethyl acetate. The combinedorganic phases were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified on a silica gel column using chloroform/methanol,(5:1) as eluent. The residue was suspended in ethyl acetate (15 mL) andstirred overnight at room temperature. The solid was filtered, dried togive 90 mg of the title compound as a yellow solid as the base. Theobtained total amount of the base was 1.37 g (59% yield). A small amountof the free base (12 mg, 0.03 mmol) was dissolved in methylenechloride/methanol, (1:1) and treated with 1 M HCl in diethyl ether at 0°C. The resulting yellow crystals were collected by filtration and washedwith diethyl ether to obtain 13 mg (100% yield) of the title compound:¹H NMR (DMSO-d6, 400 MHz) δ 10.52 (s, 1H), 8.09 (s, 1H), 7.81 (d, J=8Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.61 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.86(d, J=8 Hz, 1H), 3.62 (br s, 4H), 3.40 (s, 2H), 2.42 (br s, 4H); MS (EI)m/z 388 (M⁺), 390 (M⁺+2).

Example 805,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 79 using5,6-dibrom-1,3-dihydro-indol-2-one. The base (27% yield) was transformedto the hydrochloride salt. The salt was purified by re-crystallizationfrom chloroform/methanol/diethyl ether and the crystals were washed withdimethylsulfoxide (1 mL) to give the title compound. Yield: 4%: ¹H NMR(CDCl₃, 400 MHz) δ 8.29 (s, 1H), 7.75 (d, J=10 Hz, 1H), 7.68 (s, 1H),7.62 (s, 1H), 7.47 (d, J=10 Hz, 1H), 7.21 (s, 1H), 3.72 (br s, 4H), 3.40(s, 2H), 2.48 (br s, 4H).

Example 813-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonitrileHydrochloride

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile(0.10 g, 0.3 mmol) was dissolved in tetrahydrofuran/dioxane, (1:1, 16mL), under N₂ atmosphere and stirred at −20° C. for 5 min. To thismixture, sodium bis(trimethylsilyl)amide (1 M solution intetrahydrofuran, 0.30 mL, 0.3 mmol) was added via syringe and thereaction was allowed to stir for 20 min at ambient temperature.1-Fluoro-2,4,6-trimethylpyridinium triflate (0.112 g, 0.33 mmol) wasadded and the reaction was allowed to warm to room temperature andstirred for 16 h. The solvent was removed in vacuo and the residue wastaken up in ethyl acetate and washed with an aqueous saturated NaHCO₃solution. The organic phase was dried (Na₂SO₄) and evaporated in vacuo.The crude product was purified by preparative HPLC (column: Xterra, C₈,10 μm, 19×300 mm; eluent: 0.05 M NH₄OAc buffer/acetonitrile, 8:2-2:8)affording 50 mg (47% yield) of a yellowish brown solid. The solid (40mg, 0.11 mmol) was dissolved in methylene chloride/methanol, (1:1), andtreated with 1 M HCl in diethyl ether at 0° C. The resulting yellowcrystals were collected by filtration and washed with diethyl ether togive 18 mg (42% yield) of the title compound: ¹H NMR (DMSO-d6, 400 MHz)δ 8.42 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.50 (d, J=8Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.44 (s, 1H), 3.60 (br s, 4H), 3.54 (s,2H), 2.38 (br s, 4H): MS (EI) m/z 353 (M⁺+1).

Example 823-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrileHydrochloride

To a suspension of sodium hydride (0.09 g, 2.2 mmol, 60% dispersion inoil, pre-washed with hexane) in N,N-dimethylformamide (3 mL), cooled onan ice-bath, was added a solution of 5-cyanooxindole (0.32 g, 2.0 mmol)in N,N-dimethylformamide (3 mL). The mixture was stirred for 20 minunder a nitrogen atmosphere and the ice-bath was removed.1-Benzyl-4-[(6-chloropyridine-3-yl)sulfonyl]piperazine (0.35 g, 1.0mmol), dissolved in N,N-dimethylformamide (4 mL), was added dropwise andthe mixture was heated at 130° C. for 40 min. The solvent was evaporatedin vacuo and the residue was partitioned between methylene chloride andaqueous NaHCO₃ (pH>7). The mixture was extracted with methylenechloride. The organic layers were combined, dried (Na₂SO₄) and thesolvent was removed in vacuo. The crude product was purified on a silicagel column using chloroform/ethanol, (20:1), as the eluent. The base(120 mg) was dissolved in chloroform/methanol and a solution of HCl indiethyl ether (1 M) was added until acidic pH. The formed precipitationwas filtered and washed with diethyl ether affording 71 mg (14% yield)of the title compound as a yellow solid: ¹H NMR (DMSO-d6, 400 MHz) δ11.15 (br s, 1H), 10.54 (br s, 1H), 8.54 (br s, 1H), 8.01 (br s, 1H),7.88-7.81 (m, 1H), 7.70 (dd, J=9, 2 Hz, 1H), 7.56-7.47 (m, 2H),7.47-7.38 (m, 4H), 7.06 (d, J=8 Hz, 1H), 4.40-4.28 (m, 2H), 3.83-3.66(m, 2H), 3.23-3.04 (m, 4H), 3.04-2.88 (m, 2H); MS (ES) m/z 474 (M⁺+1).

Example 832-Hydroxy-3-(5-{[4-(3-methylbutyl)piperazin-1-yl]sulfonyl}pyridin-2-yl)-1H-indole-5-carbonitrileHydrochloride

The title compound was prepared as described for Example 82 using5-cyanooxindole and1-[(6-chloropyridin-3-yl)sulfonyl]-4-(3-methylbutyl)piperazine. Yield:5% of the title compound as a yellow solid: ¹H NMR (DMSO-d6, 400 MHz) δ1.15 (br s, 1H), 10.63 (br s, 1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.94-7.81(m, 1H), 7.73 (d, J=9 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz,1H), 3.82-3.67 (m, 2H), 3.62-3.34 (m, 2H), 3.20-2.92 (m, 6H), 1.64-1.46(m, 3H), 0.86 (d, J=6 Hz, 6H); MS (ES) m/z 454 (M⁺+1).

Example 842-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrileHydrochloride

The title compound was prepared as described for Example 82 using5-cyanooxindole and1-[(6-chloropyridin-3-yl)sulfonyl]-4-isopropylpiperazine. Yield: 30% ofthe title compound as a yellow solid; ¹H NMR (DMSO-d6, 400 MHz) δ 11.56(br s, 1H), 10.68 (br s, 1H), 8.57 (br s, 1H), 8.02 (s, 1H), 7.93-7.81(m, 1H), 7.74 (dd, J=9, 2 Hz, 1H), 7.42 (dd, J=8, 1 Hz, 1H), 7.06 (d,J=8 Hz, 1H) 3.82-3.71 (m, 2H), 3.58-3.31 (m, 3H), 3.24-1.82 (m, 4H),1.24 (d, J=7 Hz, 6H); MS (ES) m/z 304 (M⁺+1).

Example 853-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrileHydrochloride

The title compound was prepared as described for Example 82 using5-cyanooxindole and1-[(6-chloropyridin-3-yl)sulfonyl]-4-ethylpiperazine. Yield: 4% of thetitle compound as a yellow solid: ¹H NMR (DMSO-d6, 400 MHz) δ 11.15 (brs, 1H), 10.75 (br s, 1H), 8.56 (br s, 1H), 8.04 (s, 1H), 7.93-7.82 (m,1H), 7.73 (dd, J=9, 2 Hz, 1H), 7.41 (dd, J=8, 1 Hz, 1H), 7.05 (d, J=8Hz, 1H), 3.83-3.69 (m, 2H), 3.69-3.42 (m, 2H), 3.18-2.92 (m, 6H), 1.20(t, J=7.2 Hz, 3H); MS (ES) m/z 412 (M⁺+1).

Example 863-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol

To a solution of3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-pyridin-3-yl-1H-indol-2-ol(200 mg, 0.6 mmol) in ethyl acetate (60 mL) was added phosphorustrichloride (0.4 mL). A yellow precipitate was formed and the mixturewas refluxed for 3 h, and then diluted with ethyl acetate and washedwith an aqueous saturated NaHCO₃ solution. The aqueous layer wasextracted with two portions of ethyl acetate and one portion ofchloroform. The organic layers were combined, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by preparativeHPLC (column: Xterra, 19×300 mm, eluent: water/acetonitrile, (0:100 to100:0), gradient) affording 6 mg (3% yield) of the title compound as ayellow solid: ¹H NMR (DMSO-d6, 400 MHz) δ 10.50 (br s, 1H), 8.92 (d, J=2Hz, 1H), 8.49 (dd, J=4, 1 Hz, 1H), 8.12-8.06 (m, 1H), 8.02 (s, 1H),7.90-7.71 (m, 1H), 7.71-7.67 (m, 2H), 7.43 (dd, J=8, 5 Hz, 1H), 7.20 (d,J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 3.63-3.53 (m, 4H), 3.40-3.24 (m, 2H),2.42-2.34 (m, 4H); MS (ES) m/z 388 (M⁺+1).

Example 873-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 86 using3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-5-thien-2-yl-1H-indol-2-oland phosphorus trichloride. The base was dissolved inchloroform/methanol, (3:1), and a solution of HCl in diethyl ether (1 M)was added until acidic pH. The formed precipitation was filtered, washedwith diethyl ether and dried. Yield: 9% of the title compound as anyellow solid: ¹H NMR (DMSO-d6, 400 MHz) δ 11.10 (br s, 1H), 10.55 (s,1H), 8.21 (s, 1H), 8.02-7.90 (m, 1H), 7.85-7.62 (m, 2H), 7.54-7.46 (m,1H), 7.46-7.37 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.15-7.06 (m, 1H), 6.92(d, J=8 Hz, 1H), 4.24 (s, 2H), 4.03-3.89 (m, 2H), 3.84-3.51 (m, 2H),3.39-3.28 (m, 2H) 3.16-3.05 (m, 2H); MS (ES) m/s 392 (M⁺+1).

Example 885-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 86 using5-(2-furyl)-3-[5-(morpholin-4-ylmethyl)-1-oxidopyridin-2-yl]-1H-indol-2-ol.Yield: 6% of the title compound as an yellow solid: ¹H NMR (DMSO-d6, 400MHz) δ 10.26 (br s, 1H), 10.56 (s, 1H), 8.22 (s, 1H), 8.03-7.94 (m, 1H),7.83-7.71 (m, 2H), 7.66 (s, 1H), 7.30 (d, J=8 Hz, 1H), 6.98-6.86 (m,2H), 6.59-6.53 (m, 1H), 4.31-4.10 (m, 2H), 4.16-3.85 (m, 2H), 3.85-3.70(m, 2H), 3.39-3.26 (m, 2H), 3.17-3.01 (m, 2H); MS (ES) m/z 376 (M⁺+1).

Example 893-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 55 using5-nitrooxindole and1-1-[(5-bromo-6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine.Purification on a silica gel column using chloroform/methanol, (8:2), asthe eluent gave the title compound as the base: ¹H NMR (CDCl₃, 400 MHz)δ 8.78 (br s, 1H), 8.47 (br s, 1H), 8.24 (dd, J=9, 2 Hz, 1H), 7.96 (m,1H), 7.10 (d, J=9 Hz, 1H), 3.12 (m, 4H), 2.50 (t, J=5 Hz, 4H), 2.26 (s,3H).

The base was dissolved in chloroform and treated with 5 M HCl in diethylether. The hydrochloride was dried in vacuo and recrystallized frommethanol to afford of the title compound. Yield: 9.5%.

Example 903-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 55 using5-trifluoromethyloxindole. Yield: 8%: ¹H NMR (D₂O, 400 MHz) 7.87 (s,1H), 7.64 (d, J=9 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J=9 Hz, 1H), 7.29 (d,J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 4.15 (s, 2H), 4.06-3.85 (m, 4H),3.41-3.26 (m, 4H).

Example 912-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carbonitrileHydrochloride

The title compound was prepared as described for Example 55 using6-cyanooxindole (1.5 equ) and1-(6-chloropyridine-3-sulfonyl)-4-methylpiperazine (1 equ; described in:Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203).Purification on a silica gel column using chloroform/methanol/conc.NH₃(aq), (76:23:1), as the eluent gave the title compound as the base.The base was dissolved in acetone/chloroform/methanol and treated with 5M HCl in diethyl ether. The hydrochloride was dried to afford 24 mg(5.1% yield) of title compound: ¹H NMR (DMSO-d6, 400 MHz) δ 14.87 (s,1H), 11.00 (s, 1H), 10.21 (s, 1H), 8.62 (s, 1H), 7.83 (s, 2H), 7.73 (d,J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.23 (s, 1H), 3.81-3.67 (m, 2H),3.57-3.38 (m, 2H), 3.22-3.05 (m, 2H), 2.97-2.85 (m, 2H), 2.77 (s, 3H).

Example 92N-[(1-Ethylpyrrolidin-2-yl)methyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinamideHydrochloride

To a suspension of ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate(100 mg, 0.30 mmol) in toluene (5 mL) was added2-(aminomethyl)-1-ethylpyrrolidine (78 mg, 0.61 mmol) and the mixturewas cooled to 0° C. under a nitrogen atmosphere. Trimethyl aluminium(0.6 mL, 2 M in hexane, 1.2 mmol) was added dropwise during 5 min andthe reaction was heated to 70° C. over night. The reaction was quenchedwith water and an aqueous saturated NaHCO₃ solution and is extractedwith chloroform. The combined extracts were dried (Na₂SO₄) and thesolvent was evaporated in vacuo. The residue was purified on a silicagel column using chloroform/methanol/conc. NH₃(aq), (80:19:1), as theeluent. Fractions containing product were collected and evaporated invacuo and dried at 25° C. in a vacuum-cabinet over night. The residuewas dissolved in methanol/chloroform and treated with 5 M HCl in diethylether. The hydrochloride was dried in vacuo to afford 30 mg (20% yield)of title compound as an orange solid: ¹H NMR (D₂O, 400 MHz) δ 7.65 (s,1H), 7.42 (d, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.16 (s, 1H), 6.63 (d,J=9 Hz, 1H), 6.53 (d, J=8 Hz, 1H), 3.66-3.52 (m, 4H), 3.49-3.41 (m, 1H),3.13-3.02 (m, 2H), 2.23-2.16 (m, 1H), 2.05-1.88 (m, 2H), 1.87-1.76 (m,1H), 1.26 (t, J=7 Hz, 3H).

The following Examples, 93-97, was prepared as described for Example 92:

Example 936-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamideHydrochloride

Starting material: 4-(2-aminoethyl)morpholine. The formed hydrochloridewas recrystallized from methanol. Yield: 4.1%: ¹H NMR (D₂O, 400 MHz) δ7.70 (s, 1H), 7.52 (d, J=9 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.29 (s, 1H),6.78 (d, J=9 Hz, 1H), 6.64 (d, J=8 Hz, 1H), 4.05-3.75 (m, 4H), 3.65-3.62(m, 2H), 3.50-3.20 (m, 6H).

Example 946-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamideHydrochloride

Starting material: 1-methyl-4-(methylamino)piperidine. The formedhydrochloride was recrystallized from methanol. Yield: 3.3%: MS (ES) m/z410 (M⁺+1).

Example 955-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-2-olHydrochloride

Starting material: 4-(1-pyrrolidinyl)piperidine. The formedhydrochloride was recrystallized from methanol. Yield: 5.2%: MS (EI, 70eV) m/z (relative intensity) 435 (M⁺, 1), 298 (6), 282 (7), 207 (5), 174(14), 154 (17), 124 (17), 110 (100), 98 (75), 84 (26), 70 (61), 52 (23).

Example 963-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-indol-2-olHydrochloride

Starting material: 3-(dimethylamino)pyrrolidine. The formedhydrochloride was recrystallized from methanol. Yield: 1.5%: ¹H NMR(DMSO-d6, 400 MHz) δ 11.22 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.04(dd, J=9, 2 Hz, 1H), 7.91 (dd, J=9, 2 Hz, 1H), 7.73 (d, J=9 Hz, 1H),7.05 (d, J=9 Hz, 1H), 4.05-3.83 (m, 2H), 3.82-3.70 (m, 2H), 3.66-3.54(m, 1H), 2.80 (br s, 6H), 2.40-2.29 (m, 1H), 2.23-2.10 (m, 1H).

Example 97N-[2-(Dimethylamino)-1-methylethyl]-6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinamideHydrochloride

Starting material: 3-(dimethylamino)pyrrolidine. Yield: 3.2%: ¹H NMR(D₂O, 400 MHz) δ 7.85 (s, 1H), 7.60 (d, J=9 Hz, 1H), 7.47 (d, J=9 Hz,1H), 7.36 (s, 1H), 6.84 (d, J=9 Hz, 1H), 6.64 (d, J=9 Hz, 1H), 4.51-4.40(m, 1H), 3.27-3.12 (m, 2H), 2.88-2.77 (m, 6H), 1.25 (d, J=6 Hz, 3H).

Example 986-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-pyrollindin-1-ylethyl)nicotinamideFumarate

A solution of ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (200mg, 0.61 mmol) in 2-pyrrolidin-1-yl-ethylamine (1.5 mL) was heated at120° C. in a closed vessel for 24 h. The mixture was cooled to roomtemperature and diluted with water and an aqueous solution of NaHCO₃followed by extraction with chloroform. The phases were separated andevaporated in vacuo. Purification on a silica gel column usingchloroform/methanol/conc NH₃(aq), (100:15:1.5), as the eluent gave 90 mg(37% yield) of the title compound as the base. The base was converted tothe fumarate salt according to the procedure described for Example 103:MS (ES) m/z 396 (M⁺+1).

Example 993-{5-[(4-Methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-5-nitro-1H-indol-2-olFumarate

The title compound was prepared as described for Example 92 using ethyl6-(2-hydroxy-5-nitro-1H-indol-3-yl)nicotinate (1 eqv), trimethylaluminium (4 eqv), N-methylpipearzine (2 eqv) and benzene as thesolvent. The crude product was purified on a silica gel column usingchloroform/methanol/conc NH₃(aq), (100:12:1.2), as the eluent. Yield:69% of the title compound as the base. The base was converted to thefumarate salt according to the procedure described for Example 103: MS(ES) m/z 382 (M⁺+1).

Example 1006-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)nicotinamideFumarate

The title compound was prepared as described for Example 98 using ethyl6-(2-hydroxy-5-cyano-1H-indol-3-yl)nicotinate and2-pyrrolidin-1-yl-ethylamine. Yield: 13% of the title compound: ¹H NMR(on the base, CDCl₃, 300 MHz) δ 10.8 (br s, 1H), 8.80-8.52 (m, 2H),8.18-7.86 (m, 3H), 7.35-7.18 (m, 1H), 6.98 (d, J=7 Hz, 1H), 6.55 (s,1H), 3.60-3.35 (m, 2H), 2.83 (m, 6H), 1.80 (br s, 4H).

Example 1016-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamideHydrochloride

To an ice-cooled solution of 5-cyanooxindole (200 mg, 1.26 mmol) inN,N-dimethylformamide (5 mL) was added sodium hydride (60 mg, 1.5 mmol).The reaction mixture was stirred for 25 min whereafter6-chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide (303mg, 1 mmol) was added. The reaction mixture was heated at 130° C. for 1h and then allowed to cool to room temperature. An aqueous saturatedsolution of NaHCO₃ (50 mL) was added and the water phase was extractedwith ethyl acetate. The organic phase was dried (Na₂SO₄) and purified ona silica gel column using chloroform/methanol/conc NH₃(aq), (500:35:3.5to 500:50:5), as the eluent. The solvents were evaporated in vacuo andthe residue was stirred over night in ethyl acetate, filtered and driedto give 160 mg (38% yield) of the title compound as the base. The base,dissolved in chloroform/methanol, was treated with HCl in diethyl etherto give the title compound: MS (ES) m/z 426 (M⁺+1).

Example 1026-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamideFumarate

The title compound was prepared as described for Example 101 using6-chloro-N-[2-(dimethylamino)ethyl]pyridine-3-sulfonamide and5-cyanooxindole. The crude product was purified on a silica gel columnusing chloroform/methanol/conc NH₃(aq), (100:10:1), as the eluentfollowed by another purification on a silica gel column usingchloroform/methanol/conc NH₃(aq), (100:7:0.7), as the eluent. The basewas converted to the fumarate salt according to the procedure describedfor Example 103: Yield: 20%: MS (ES) m/z 386 (M⁺+1).

Example 1036-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamideFumarate

The title compound was prepared as described for Example 101 using6-chloro-N-[2-(dimethylamino)ethyl]-N-ethylpyridine-3-sulfonamide and5-cyanooxindole. The crude product was purified on a silica gel columnusing chloroform/methanol/conc NH₃(aq), (100:10:1), as the eluent: MS(ES) m/z 414 (M⁺+1). The base was dissolved in chloroform (15 mL) andmethanol (2 mL) and fumaric acid dissolved in methanol (2 mL) was added.Diethyl ether (20 mL) was added and the formed precipitate was filteredand dried to give the title compound. Yield: 10%: MS (ES) m/z 414(M⁺+1).

Example 1046-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamideFumarate

The title compound was prepared as described for Example 101 using6-chloro-N-[(1-ethylpyrrolidin-2-yl)methyl]pyridine-3-sulfonamide and5-cyanooxindole. The crude product was purified on a silica gel columnusing chloroform/methanol/conc NH₃(aq), (100:18:1.8), as the eluent.Yield: 50%: MS (ES) m/z 426 (M⁺+1). The base was converted to thefumarate salt according to the procedure described for Example 103.

Example 1052-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrileFumarate

The title compound was prepared as described for Example 101 using1-[(6-chloropyridin-3-yl)sulfonyl]-4-methyl-1,4-diazepane and5-cyanooxindole. The crude product was purified on a silica gel columnusing chloroform/methanol/conc NH₃(aq), (100:15:1.5), as the eluent.Yield: 50%: MS (ES) m/z 412 (M⁺+1). The base was converted to thefumarate salt according to the procedure described for Example 103.

Example 1062-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitrile

The title compound was prepared as described for Example 101 using4-[(6-chloropyridin-3-yl)sulfonyl]morpholine and 5-cyanooxindole. Thereaction mixture was quenched with water and the solvents wereevaporated in vacuo. Water was added and the mixture was filtered. Thesolid material was washed with water, methanol, ethyl acetate anddiethyl ether to give the title compound. Yield: 44%: MS (ES) m/z 385(M⁺+1).

Example 1073-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indol-2-olHydrochloride

The title compound was prepared as described for Example 101 using1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (described in:Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and5-(2-methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one. The crudeproduct was purified on a silica gel column usingchloroform/methanol/conc NH₃(aq), (50:3:0.3), as the eluent. The basewas dissolved in chloroform/methanol and converted to the hydrochloridesalt using HCl in diethyl ether (1 M). Yield: 35% of the title compound:MS (ES) m/z 470 (M⁺+1).

Example 1083-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-thiazol-4-yl)-1H-indol-2-olFumarate

The title compound was prepared as described for Example 101 using1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (described in:Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and5-(1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one. The crude product waspurified on a silica gel column using chloroform/methanol/conc NH₃(aq),(100:7:0.7), as the eluent. The base was converted to the fumarate saltaccording to the procedure described for Example 103: Yield: 8% of thetitle compound: MS (ES) m/z 456 (M⁺+1)

Example 1093-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(1,3-oxazol-5-yl)-1H-indol-2-ol

The title compound was prepared as described for Example 101 using1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (described in:Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one. The crude product waspurified on a silica gel column using chloroform/methanol/conc NH₃(aq),(100:10:1), as the eluent followed by trituration in ethyl acetate.Yield: 1% of the title compound: MS (ES) m/z 441 (M⁺+1).

Example 1103-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-olHydrochloride

To a suspension of sodium hydride (60% dispersion in oil, 0.048 g, 1.19mmol, pre-washed with hexane) in N,N-dimethylformamide (2.0 mL) wasadded 5-nitrooxindole (0.185 g, 1.04 mmol). The formed mixture wasstirred for 5 min at room temperature and2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (0.16 g, 0.7 mmol) wasadded. The resulting reaction mixture was stirred for 30 minutes at 130°C. (N₂ atmosphere). The solvent was removed in vacuo and the residualoil was purified on a silica gel column using chloroform/methanol,(10:1) as the eluent affording the N-oxide product. The N-oxide wasdissolved in chloroform (2 mL) and phosphorous trichloride (0.385 g,2.80 mmol) was added. The reaction mixture was stirred for 30 min at 60°C. followed by extraction with an aqueous saturated NaHCO₃ solution. Theorganic layer was dried (Na₂SO₄) and concentrated to a yellowish red oilwhich was purified on a silica gel column using chloroform/methanol,(10:1) as the eluent to give 10 mg (4% yield) of the title compound asthe free base as an yellow solid. The base (10 mg, 0.028 mmol) wasdissolved in methylene chloride/methanol, (1:1) and treated with 1 M HClin diethyl ether at 0° C. The resulting yellowish orange crystals werecollected by filtration and washed with diethyl ether to obtain 2 mg(16% yield) of the title compound: ¹H NMR (DMSO-d6, 400 MHz) δ 11.23 (s,1H), 10.83 (br s, 1H), 8.36 (s, 2H), 8.10 (dd, J=10, 2 Hz, 1H), 7.94(dd, J=9, 2 Hz, 1H), 7.87 (d, J=10 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.34(s, 2H), 4.02 (d, J=13 Hz, 2H), 3.77 (t, J=12 Hz, 2H), 3.38 (d, J=11 Hz,2H), 3.14 (d, J=0 Hz, 2H).

Pharmacology Determination of ATP Competition in Scintillation ProximityGSK3β Assay GSK3b Scintillation Proximity Assay.

The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3β (Dundee University,UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by theaddition of 0.04 μCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 minutes at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicroBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSK3β, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

The following abbreviations have been used:MOPS Morpholinepropanesulfonic acidEDTA Ethylenediaminetetraacetic acid

BSA Bovin Serum Albumin ATP Adenosine Triphosphate SPA ScintillationProximity Assay

GSK3 Glycogen synthase kinase 3MP-Carbonate Macroporous triethylamonium methylpolystyrene carbonate

PS-Diisopropylethylamine N,N-(Diisopropyl)aminomethylpolystyrenePS-Thiophenol 3-(3-Mercaptophenyl)propanamidomethylpolystyrene

PS-Isocyanate Polystyrene methylisocyanate

RESULTS

Typical K_(i) values for the compounds of the present invention are inthe range of about 0.001 to about 10,000 nM. Other values for K_(i) arein the range of about 0.001 to about 1000 nM. Further values for K_(i)are in the range of about 0.010 nM to about 300 nM.

1-41. (canceled)
 42. A method of prevention and/or treatment ofconditions associated with glycogen synthase kinase-3, comprisingadministering to a mammal, including man in need of such preventionand/or treatment, a therapeutically effective amount of a compound offormula Ia

wherein the compound is in the form of a base or a pharmaceuticallyacceptable salt thereof, and wherein: P is a 6-membered ring containingone nitrogen; R¹ is hydrogen; R² is C₀₋₆alkylcyano; R³ isC₀₋₆alkylNR⁴R⁵; m is 1; n is 1; R⁴ is selected from the group consistingof hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl,C₁₋₆alkylNR¹⁴R¹⁵, and a 5- or 6-membered heterocyclic group containingone or two heteroatoms independently selected from N, O, and S, whereinthe heterocyclic group is optionally substituted by a group Y; R⁵ isselected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl, and C₁₋₆alkylNR¹⁴R¹⁵; or R⁴ and R⁵ together withthe N to which they are attached may form a 6-membered heterocyclicgroup containing one nitrogen and one oxygen; and wherein any C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, andC₀₋₆alkylheteroaryl group defined under R² to R⁵ is optionallysubstituted by one or more groups Z; R¹⁴ and R¹⁵ are independentlyselected from hydrogen, C₁₋₆alkyl, and C₀₋₆alkylC₃₋₆cycloalkyl, whereinR¹⁴ and R¹⁵ optionally together form a 5- or 6-membered heterocyclicgroup containing one or more heteroatoms independently selected from N,O, and S, wherein the heterocyclic group is optionally substituted by agroup Y; Z is independently selected from the group consisting of oxo,halogen, nitro, CN, OR¹⁶, C₁₋₆alkyl, C₀₋₆alkylaryl,C₀₋₆alkylC₃₋₆cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC₁₋₆alkylNR¹⁶R¹⁷,NR¹⁶R¹⁷, CONR¹⁶R¹⁷NR¹⁶(CO)R¹⁷, O(CO)C₁₋₆alkyl, (CO)OC₁₋₆alkyl, COR¹⁶,(SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶, (CO)C₁₋₆alkylNR¹⁶R¹⁷,(SO₂)C₁₋₆alkylNR¹⁶R¹⁷, phenyl, heteroaryl, and a 5- or 6-memberedheterocyclic group containing one or two heteroatoms independentlyselected from N, O, and S, wherein the phenyl, heteroaryl, andheterocyclic groups are optionally substituted by a group Y; Y isselected from the group consisting of oxo, halogen, nitro, CN, OR¹⁶,C₁₋₆alkyl, C₀₋₆alkylaryl, C₀₋₆alkylC₃₋₆cycloalkyl, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, OC₁₋₆alkylNR¹⁶R¹⁷, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶(CO)R¹⁷,O(CO)C₁₋₆alkyl, (CO)OC₁₋₆alkyl, COR¹⁶, (SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶,(CO)C₁₋₆alkylNR¹⁶R¹⁷ (SO₂)C₁₋₆alkylNR¹⁶R¹⁷, phenyl, C₀₋₆alkylaryl, andheteroaryl, wherein the phenyl, C₀₋₆alkylaryl, and heteroaryl groups areoptionally substituted with one or more substituents selected from thegroup consisting of halogen, nitro, CN, OR¹⁶, C₁₋₆alkyl, fluoromethyl,difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, andtrifluoromethoxy; R¹⁶ and R¹⁷ are independently selected from hydrogenand C₁₋₆alkyl, and wherein R¹⁶ and R¹⁷ optionally together form a 5- or6-membered heterocyclic group containing one or more heteroatomsindependently selected from N, O, and S.
 43. A method according to claim42 wherein in said compound of formula Ia, R⁵ is C₁₋₆ylNR¹⁴R¹⁵, and R⁴is selected from hydrogen, C₁₋₆alkyl; or R⁴ and R⁵ together with the Nto which they are attached form a 6-membered heterocyclic groupcontaining one or more heteroatoms selected independently from N and O,wherein said heterocyclic group may optionally be substituted by a groupY; and wherein R¹⁴ and R¹⁵ may together form a 5-membered heterocyclicgroup containing one or more heteroatoms, selected independently from N,and O Y is selected from C₁₋₆alkyl, C₀₋₆alkylaryl, NR¹⁶R¹⁷, phenyl,wherein the phenyl may be optionally substituted with nitro andtrifluoromethyl; wherein R¹⁶ and R¹⁷ may together form a 5-memberedheterocyclic group containing one N heteroatom, in the form of a base ora pharmaceutically acceptable salt thereof.
 44. A method according toclaim 42 wherein in said compound of formula Ia, P is pyridyl; R² is CN;R³ is C₀₋₆alkylNR⁴R⁵; wherein R⁴ and R⁵ may together form a 5- or6-membered heterocyclic group containing one or more heteroatomsselected independently from N and O, in the form of a base or apharmaceutically acceptable salt thereof.
 45. A method according toclaim 42 wherein in said compound of formula Ia, R⁴ and R⁵ together forma 6-membered heterocyclic group containing one or more heteroatomsselected independently from N and O, in the form of a base or apharmaceutically acceptable salt thereof.
 46. A method according toclaim 42 wherein in said compound of formula Ia is a compound selectedfrom:2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbonitrile;3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile;2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol, or2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitrile;or a pharmaceutically acceptable salt thereof.
 47. A method according toclaim 42 wherein in said compound of formula Ia is a compound selectedfrom:2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-(pyrrolidin-1-ylmethyl)pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonitrile;3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol;5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol;3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-ol;6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide;6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamide;5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-2-ol;3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-indol-2-ol;6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indol-2-ol;3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile;5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol, or2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carbonitrile;or a pharmaceutically acceptable salt thereof.
 48. A method ofprevention and/or treatment according to claims 42 wherein saidcondition associated with glycogen synthase kinase-3 is selected from:dementia, Alzheimer's Disease, Parkinson's Disease, Frontotemporaldementia Parkinson's Type, Parkinson dementia complex of Guam, HIVdementia, diseases with associated neurofibrillar tangle pathologies anddementia pugilistica.
 49. A method according to claim 48, wherein thecondition is Alzheimer's Disease.
 50. A method of prevention and/ortreatment according to claim 42 wherein said condition is selected from:amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, postencephalitic parkinsonism, progressivesupranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, headtrauma and other chronic neurodegenerative diseases, Bipolar Disease,affective disorders, depression, schizophrenia or cognitive disorders.51. A method of prevention and/or treatment according to claim 42wherein said condition is selected from: predemented states, MildCognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Impairment No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment, vascular dementia, dementia withLewy bodies or Frontotemporal dementia.
 52. A method according to claim50 wherein the condition is Bipolar Disease.